Quinazoline pan-kras inhibitors

Abstract

The present invention relates to compounds that inhibit at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, pharmaceutical compositions comprising the compounds and methods of use therefor.

Description

QUINAZOLINE PAN-KRas INHIBITORS FIELD OF THE INVENTION

[0001] The present invention relates to compounds that inhibit multiple mutated forms of KRas, i.e., pan-KRas inhibitors. In particular, the present invention relates to pan-KRas compounds, pharmaceutical compositions comprising the compounds and methods of use therefor. BACKGROUND OF THE INVENTION

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol.13:394-401).

[0003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas. KRas mutations at codons 12, 13, 61 and other positions of the KRas primary amino acid sequence are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colon / rectal adenocarcinoma patients, and 32% lung adenocarcinoma patients (e.g., see Prior et all., (2020) Cancer Res 80:2969–74). A recent publication also suggested wild type Kras inhibition could be a viable therapeutic strategy to treat KRasWTdependent cancers (e.g., see Bery et al., (2020) Nat. Commun.11: 3233).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractive target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large-scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor has yet demonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res.21 (8):1797-1801).

[0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett.9:1230-1234). Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants.

[0006] Thus, there is a need to develop new pan-KRas inhibitors that demonstrate sufficient efficacy for treating KRas-mediated cancers. SUMMARY OF THE INVENTION

[0007] In one aspect of the invention there are provided compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0008] A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R1;

[0009] B is:

[0010] Y1is hydrogen, hydroxy, halogen, C1-C4 alkyl, L-C3-C6 cycloalkyl optionally substituted with 1-4 R9, L-heteroaryl optionally substituted with 1-4 R8, L-aryl optionally substituted with 1-4 R8, L-C(O)-NH2, and L-heterocycle optionally substituted with 1-2 oxo (=O) or oxo-containing substituent, and optionally further substituted with 1-2 R8;

[0011] Y2is hydrogen or C1-C4 alkyl;

[0012] or Y1and Y2join to form:where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-;

[0013] each R1is independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl , triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1- C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;

[0014] each R2is independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, - OC(O)N(R5)2, -CO2R5, or -CO2N(R5)2;

[0015] each R3is independently hydrogen, deuterium hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, - COC(O)N(R5)2, -CO2R5, or -CO2N(R5)2;

[0016] R4is hydrogen, halogen or C1 – C3 alkyl;

[0017] each R5is independently hydrogen or C1-C3 alkyl;

[0018] each R6is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl;

[0019] each R7is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -CN, aryl, -CH2-S(O)2NH2, or heteroaryl optionally independently substituted with 1-2 C1-C3 alkyl, -CN or C(O)NH2,

[0020] two R7on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1- C3 alkyl),

[0021] two R7on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R8, heteroaryl optionally substituted with 1-4 R8, aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8, and

[0022] two R7on non-adjacent atoms optionally join to form a bridge comprising 1-3 members selected from (i) -CH2- optionally substituted with 1-2 substituents selected from hydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-;

[0023] each R8is independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN;

[0024] each R9is independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN;

[0025] R10is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1- C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl;

[0026] L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)- or cyclopropyl-CH2-;

[0027] Z is C or O, wherein if Z is C the 6-membered ring that includes Z is aromatic, and wherein if Z is O the 6-membered ring that includes Z is an oxane;

[0028] each n is 0-3;

[0029] o is 1-6; and

[0030] p is 1-8.

[0031] In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0032] In yet another aspect of the invention, methods for inhibiting the activity of cells containing wild type KRas or one or more KRas mutations, for instance the KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, in a in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0033] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0034] Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0035] Also provided herein is a method of treating a KRas wild type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0036] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0037] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0038] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the inhibition of KRas wild type or multiple types of KRas mutations, for instance KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0039] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas wild type associated disease or disorder or a KRas mutation G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder.

[0040] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0041] Also provided herein is a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of  activity of the wild type form of KRas or mutated forms of KRas, including the mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0042] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas wild type associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder.

[0043] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with KRas wild type or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (i.e., a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0044] One potential utility of the herein-described pan-KRas inhibitors, including pan- KRas inhibitors such as 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Example 23 herein), is for the treatment of cancers that develop resistance following long-term treatment with KRas G12C inhibitors. Thus, embodiments of the invention include those wherein a patient suffering from cancer is treated with a herein-described pan-KRas inhibitor such as Example 5 after treatment with a G12C inhibitor becomes ineffective or less effective due to the emergence of resistance- imparting mutations.

[0045] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors such as adagrasib (MRTX849) or sotorasib (AMG510) may result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations could confer resistance through numerous mechanisms.

[0046] Mutations that change the mutant cysteine at codon 12 to another amino acid would render the current covalent KRas G12C inhibitors ineffective since current inhibitors make a covalent bond with the mutant cysteine amino acid side chain. Likewise, in patients that have one wild type KRas allele in addition to the KRas G12C-mutant allele, mutations in the wild type  codon 12 glycine to another codon would allow bypass signaling in these tumors through the novel mutant protein. The repertoire of codon 12 mutations that can occur with a single nucleotide substitution in the wild type gene (glycine codon) includes mutations commonly observed in cancer such as G12S, G12V, G12R, G12C. The repertoire of codon 12 mutations that can occur with single nucleotide base substitutions of the cysteine codon 12 include mutations not frequently observed in cancer, G12Y, G12F and G12W, in addition to G12S and G12R.

[0047] Second-site mutations may also occur in another location in the KRas G12C mutant gene that confers resistance to KRas G12C inhibitor treatment. These mutations may confer resistance through different mechanisms. RAS proteins are small GTPases that normally cycle between an active, GTP-bound state and an inactive, GDP-bound state. RAS proteins are loaded with GTP through guanine nucleotide exchange factors (GEFs; e.g., SOS1) which are activated by upstream receptor tyrosine kinases, triggering subsequent interaction with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity which is dramatically enhanced by GTPase-activating proteins (GAPs). Mutations at codons 12 and 13 in RAS proteins impair GAP-stimulated GTP hydrolysis leaving RAS predominantly in the GTP-bound, active state. Covalent KRas G12C inhibitors in current clinical development only bind GDP-bound KRas G12C. Mutations such as Q61 codon mutations, which may or may not occur on the same allele as the G12C mutation, reduce the intrinsic GTPase activity of KRas and may represent a mechanism of resistance to KRas G12C inhibitor treatment by shifting KRas into the GTP-loaded state where it is not susceptible to covalent inhibition. Co- mutations such as R68, H95 and Y96 may be present along with the KRas G12C mutation and may diminish the binding affinity of KRas G12C inhibitors to the Switch II binding pocket.

[0048] The herein-described pan-KRas inhibitors may demonstrate activity against common as well as uncommon codon 12 mutations or mutations that occur in the KRas protein that diminish binding of KRas G12C inhibitors to the KRas protein.

[0049] Also provided herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0050] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.  DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention relates to inhibitors of KRas wild type and / or multiple mutated forms of KRas, for instance KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations. In particular, the present invention relates to compounds that inhibit the activity of KRas wild type and / or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor. DEFINITIONS

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.

[0053] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labelled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the present invention and prodrugs thereof can generally be  prepared by carrying out the procedures below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0054] As used herein, “wild type KRas” refers to a non-mutant form of a mammalian KRas protein. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “wild type KRas inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of wild type KRas G12A. A "wild type KRas-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having wild type KRas. A non-limiting example of a wild type KRas-associated disease or disorder is a wild type KRas-associated cancer.

[0055] As used herein, “KRas G12A” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12A inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12A. A "KRas G12A-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12A mutation. A non-limiting example of a KRas G12A-associated disease or disorder is a KRas G12A-associated cancer.

[0056] As used herein, “KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12C inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. A "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by  or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12CD-associated cancer.

[0057] As used herein, “KRas G12D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12D inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12D. A "KRas G12D- associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation. A non-limiting example of a KRas G12D- associated disease or disorder is a KRas G12D-associated cancer.

[0058] As used herein, “KRas G12R” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12R inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12R. A "KRas G12R-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is a KRas G12R-associated cancer.

[0059] As used herein, “KRas G12S” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12S inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12S. A "KRas G12S-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by  or having a KRas G12S mutation. A non-limiting example of a KRas G12S-associated disease or disorder is a KRas G12S-associated cancer.

[0060] As used herein, “KRas G12V” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G12V inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12V. A "KRas G12V-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12V mutation. A non-limiting example of a KRas G12V-associated disease or disorder is a KRas G12V-associated cancer.

[0061] As used herein, “KRas G13D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas G13D inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G13D. A "KRas G13D- associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G13D mutation. A non-limiting example of a KRas G13D- associated disease or disorder is a KRas G13D-associated cancer.

[0062] As used herein, “KRas Q61H” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, a “KRas Q61H inhibitor” refers to compounds of the present invention that are represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas Q61H. A "KRas Q61H-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by  or having a KRas Q61H mutation. A non-limiting example of a KRas Q61H-associated disease or disorder is a KRas Q61H-associated cancer.

[0063] As used herein, the term “subject,” "individual," or "patient," used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (e.g., as determined using a regulatory agency- approved assay or kit). The subject can be a subject with a tumor(s) that is positive for wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0064] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has wild type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having wild type KRas-associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer, a patient having one or more symptoms of wild type KRas-  associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer, and / or a patient that has an increased risk of developing wild type KRas-associated or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT- PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.

[0065] The term “regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0066] The term "acyl" refers to -C(O)CH3.

[0067] The terms "C1-C6 alkyl", “C1-C4 alkyl” and “C1-C3 alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, respectively. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0068] The terms “C1-C3 haloalkyl” and “C1-C4 haloalkyl” refer to a C1-C3 alkyl chain or C1-C4 alkyl chain, respectively, as defined herein in which one or more hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0069] An "C1-C4 alkylene," group is a C1-C4 alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.

[0070] The terms “C1-C3 alkoxy” and “C1 – C4 alkoxy” refer to –OC1 – C3 alkyl and - OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined herein above.

[0071] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted with one or more R8or R9groups as defined herein. Examples of cycloalkyl groups  include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term “cycloalkyl” also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.

[0072] As used herein, the terms “C1-C3 hydroxyalkyl” and “C1-C4 hydroxyalkyl” refer to –C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0073] As used herein, the term “C2-C4 hydroxyalkynyl” refers to -C2-C4 alkynylene- OH.

[0074] An "aryl" group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted with one or more R8or R9groups as defined herein. As one embodiment, the aryl group is a C6-C10aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. “Aryl” also refers to bicyclic or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated, and wherein if said ring system includes two saturated rings, said saturated rings may be fused or spirocyclic. An example of an aryl ring system comprising two saturated rings wherein the rings are spirocyclic includes the following ring system:.

[0075] An "araC1-C6 alkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. An example of an aralkyl group is (C6-C10)aryl(C1- C6)alkyl-, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An example of a substituted araC1-C6 alkyl is wherein the alkyl group is substituted with hydroxyalkyl.

[0076] A "heterocyclyl" or "heterocyclic" group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted with one or more R8or R9groups on ring carbon or ring nitrogen at one or more  positions, wherein R6is as defined for Formula I. The heterocyclic group is also independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H- pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1H)-oxide, tetrahydro- 2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0077] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring, or from one to three heteroatoms in at least one ring, selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-  thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. “Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0078] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of one or more of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0079] As used herein, a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of one or more of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0080] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0081] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition. COMPOUNDS

[0082] In one embodiment of the invention there are provided compounds of Formula (I):  or a pharmaceutically acceptable salt thereof, wherein:

[0083] A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R1;

[0084] B is:;

[0085] Y1is hydrogen, hydroxy, halogen, C1-C4 alkyl, L-C3-C6 cycloalkyl optionally substituted with 1-4 R9, L-heteroaryl optionally substituted with 1-4 R8, L-aryl optionally substituted with 1-4 R8, L-C(O)-NH2, and L-heterocycle optionally substituted with 1-2 oxo (=O) or oxo-containing substituent, and optionally further substituted with 1-2 R8;

[0086] Y2is hydrogen or C1-C4 alkyl;

[0087] or Y1and Y2join to form:  where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-;

[0088] each R1is independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl , triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1- C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;

[0089] each R2is independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, - OC(O)N(R5)2, -CO2R5, or -CO2N(R5)2;

[0090] each R3is independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, - COC(O)N(R5)2, -CO2R5, or -CO2N(R5)2;

[0091] R4is hydrogen, halogen or C1 – C3 alkyl;

[0092] each R5is independently hydrogen or C1-C3 alkyl;

[0093] each R6is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl;

[0094] each R7is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -CN, aryl, -CH2-S(O)2NH2, or heteroaryl optionally independently substituted with 1-2 C1-C3 alkyl, -CN or C(O)NH2,

[0095] two R7on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1- C3 alkyl),

[0096] two R7on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R8, heteroaryl optionally substituted with 1-4 R8, aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8, and

[0097] two R7on non-adjacent atoms optionally join to form a bridge comprising 1-3members selected from (i) -CH2- optionally substituted with 1-2 substituents selected fromhydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-;

[0098] each R8is independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN;

[0099] each R9is independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; [000100] R10is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1- C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl ; [000101] L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)- or cyclopropyl-CH2-; [000102] Z is C or O, wherein if Z is C the 6-membered ring that includes Z is aromatic, and wherein if Z is O the 6-membered ring that includes Z is an oxane; [000103] each n is 0-3; [000104] o is 1-6; and [000105] p is 1-8.  [000106] Such embodiment can include compounds or salts wherein: [000107] A is aryl, optionally substituted with 1-4 R1; [000108] Y1and Y2join to form:where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-; [000109] each R1is independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl , triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1- C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, or (C1-C3 alkoxy)haloC1-C3 alkyl-; [000110] each R6is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl; [000111] each R7is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -CN, or -CH2-S(O)2NH2, [000112] two R7on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1- C3 alkyl), [000113] two R7on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R8, heteroaryl optionally substituted with 1-4 R8, aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8, and  [000114] two R7on non-adjacent atoms optionally join to form a bridge comprising 1-3 members selected from (i) -CH2- optionally substituted with 1-2 substituents selected from hydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-; [000115] each R8is independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN; [000116] R10is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1- C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; [000117] L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)- or cyclopropyl-CH2-; [000118] Z is C or O, wherein if Z is C the 6-membered ring that includes Z is aromatic, and wherein if Z is O the 6-membered ring that includes Z is an oxane; [000119] each n is 0-3; and [000120] p is 1-8. [000121] In some embodiments described herein, B is:. [000122] In some embodiments described herein B is di-methyl amino. [000123] In some embodiments, A is naphthyl. [000124] In certain embodiments, -L-B is:  . [000125] In certain embodiments, A is indazolyl. [000126] In certain embodiments, A is benzothiophenyl. [000127] In some embodiments described herein, at least one R1is C1-C4 alkyl. [000128] In certain embodiments described herein, at least one R1is halogen, and is preferably fluorine. [000129] In some embodiments described herein, at least one R1is hydroxy. [000130] In some embodiments described herein, at least one R2is halogen, and is preferably fluorine. [000131] In certain embodiments of the invention, at least one R3is halogen, and is preferably fluorine. [000132] In certain embodiments of the invention, at least one R3is selected from the group consisting of ethenyl, fluoro ethenyl, and di-fluoro ethenyl. [000133] In certain embodiments of the invention, R4is halogen, and is preferably fluorine. [000134] In certain embodiments of the invention, one or both R6are C1-C4 alkyl. [000135] In certain embodiments of the invention, one or both R6are hydrogen. [000136] In certain embodiments of the invention described herein, two R7on the same atom join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with one or more substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl). [000137] In certain embodiments of the invention described herein, two R7on adjacent atoms join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-  4 R8; heteroaryl optionally substituted with 1-4 R8; aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8. [000138] In certain embodiments of the invention, two R7on non-adjacent atoms join to form a bridge comprising 1-3 members selected from (i) -CH2- optionally substituted with 1-2 substituents selected from hydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-; [000139] In certain embodiments of the invention, at least one R8is C1-C4 alkyl. [000140] In certain embodiments of the invention, at least one R8is hydroxy or C1-C3 alkyl- hydroxy. [000141] In certain embodiments of the invention, one or two R8are oxo (=O). [000142] In certain embodiments of the invention, Y1and Y2join to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bound to a fused ring via nitrogen or thiomorpholine. [000143] Non-limiting examples of compounds of Formula (I) are selected from the group consisting of:    and pharmaceutically acceptable salts thereof. [000144] In one embodiment, the compounds of Formula (I) include bis-hydrochloride, tris- hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoracetic acid salts of the above compounds. The compounds of Formula (I) or pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions. PHARMACEUTICAL COMPOSITIONS [000145] In another aspect, the invention provides pharmaceutical compositions comprising a wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection,  intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, intrarectal, subcutaneous, and topical administration. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route. In some embodiments, the provided pharmaceutical compositions may be administered to a subject in need of treatment by injection systemically, such as by intravenous injection; or by injection or application to the relevant site, such as by direct injection via syringe, or direct application to the site when the site is exposed in surgery; or by topical administration. [000146] Parenteral administration can be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. [000147] The provided pharmaceutical compositions can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulations may be modified with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [000148] The pharmaceutical compositions may, if desired, be presented in a vial, pack or a medical device, including but not limited to a dispenser device which may contain one or more unit dosage forms containing the active ingredient. In one embodiment the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection. The syringe can be accompanied by instructions for administration. [000149] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of  pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990. [000150] As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). [000151] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. In one embodiment, a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg / kg, for example 0.1 to 100 mg / kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. [000152] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods of use described herein. METHODS OF USE  [000153] In yet another aspect, the invention provides for methods for inhibiting wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or KRas Q61H activity in a cell, comprising contacting the cell in which inhibition of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or Q61H activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. [000154] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation.. [000155] In one embodiment, a cell in which inhibition of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof to negatively modulate the activity of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H. [000156] By negatively modulating the activity of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen  to affect the desired negative modulation of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H. The ability of compounds to bind one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H may be monitored in vitro using well known methods, including those described in Examples A and B below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of one or more of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity of the amount of phosphorylated ERK, for example using the method described in Example C below. [000157] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. [000158] The compositions and methods provided herein may be used for the treatment of a wild type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In one embodiment, the wild type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated cancer is lung cancer. [000159] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell,  adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant  melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer. [000160] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post- operatively. [000161] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [000162] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. [000163] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H. [000164] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of wild type KRas-associated or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated disease or disorder. [000165] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.  [000166] Also provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of wild type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H. [000167] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of wild type KRas-associated or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated disease or disorder. [000168] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000169] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. [000170] One skilled in the art will further recognize that human clinical trials including first- in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts. REACTION SCHEMES AND EXAMPLES [000171] The compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art. For instance, compounds of the present invention may be prepared according to the reaction schemes and examples outlines below.  [000172] The compounds of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term “compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms. [000173] The compounds of the present invention may be in anhydrous, solvated or hydrated forms, and all such forms are included within the scope of the invention. [000174] The following Examples are intended to illustrate further certain embodiments ofthe invention and are not intended to limit the scope of the invention.[000175] EXAMPLE 1(1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol  [000176] Step A. 7-bromo-2-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 2,2,2-trifluoroethanol (3.45 g, 1.2 equiv) in THF (36 mL) was added NaH (1.38 g, 60% purity, 1.2 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then the mixture was added to a solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (8.50 g, 1.0 equiv) in THF (64 mL) at -40 °C. The mixture was stirred at -40 °C for 1 hour. The mixture was diluted with saturated NH4Cl aqueous solution (80 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) and concentrated under vacuum to afford the title compound (9.10 g, 88% yield) as yellow solid;1H NMR (400 MHz, CDCl3-d) δ = 7.87 (dd, J = 1.2, 8.8 Hz, 1H), 7.77 (dd, J = 6.0, 8.8 Hz, 1H), 5.02 (q, J = 8.0 Hz, 2H) [000177] Step B. 1-[1-[[7-bromo-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2- yl]oxymethyl]cyclopropyl]-N,N-dimethyl-methanamine: To a solution of 7-bromo-2-chloro-8- fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (1.00 g, 1.0 equiv) and [1- [(dimethylamino)methyl]cyclopropyl]methanol (395 mg, 1.1 equiv) in dioxane (10 mL) was added Na2CO3 (884 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) and concentrated to afford the title compound (650 mg, 52% yield) as yellow oil; LCMS (ESI, M+3): m / z = 454.1.  [000178] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 1-[1-[[7- bromo-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl]oxymethyl]cyclopropyl]-N,N- dimethylmethanamine (750 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-ol (629 mg, 1.2 equiv) in CPME (7 mL) were added Cs2CO3 (1.5 M, 3.3 mL, 3.0 equiv) and Ad2nBup-Pd-G3 (242 mg, 0.2 equiv). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with EtOAc (8 mL × 3). The organic layer was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc =1 / 0 to 0 / 1) and concentrated to afford the title compound (740 mg, 79% yield) as brown solid; LCMS (ESI, M+1): m / z = 562.0. [000179] Step D. (1S,5S,6S)-3-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-quinazolin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (250 mg, 1.0 equiv) and (1S,5S,6S)-3-azabicyclo[3.2.1]octan-6-ol (68.0 mg, 1.2 equiv) in DMF (1 mL) and ACN (1 mL) was added K3PO4 (283 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep- HPLC [Phenomenex Synergi C18150 × 25 mm × 10um; A: water (FA), B: ACN, B%: 23%-53% over 10 min] and concentrated to remove ACN. The aqueous phase was adjusted to pH = 7 with saturated NaHCO3 aqueous solution and extracted with DCM (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The impurity was further purified prep- HPLC [Phenomenex luna C18150 × 25 mm × 10 um; A: water (FA), B: ACN, B%: 17%-47% over 12 min] and lyophilized to afford the title compound (53.06 mg, 19% yield) as white solid; SFC: Rt = 0.660 min, 1.511 min; column: Chiralpak IC-350×4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for EtOH (0.05% DEA); gradient elution: 50% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temp: 35 °C; back pressure: 100 Bar.1H NMR (400 MHz, DMSO-d6) δ = 8.22 - 8.08 (m, 2H), 7.75 (dd, J = 6.0, 8.8 Hz, 1H), 7.34 (t, J = 9.4 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.22 (br t, J = 7.6 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.26 - 4.13 (m, 3H), 3.52 (br t, J = 10.2 Hz, 1H), 3.28 (br dd, J = 7.2, 12.4 Hz, 1H),  2.40 - 2.25 (m, 6H), 2.21 (s, 6H), 2.13 - 2.03 (m, 2H), 1.76 - 1.60 (m, 2H), 1.36 (br d, J = 13.2 Hz, 1H), 0.74 - 0.67 (m, 3H), 0.66 - 0.61 (m, 2H), 0.41 (s, 2H); LCMS (ESI, M+1): m / z = 589.3. [000180] EXAMPLE 2(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000181] Step A. (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3- ol: To a solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (1.60 g, 1.0 equiv), DIEA (2.23 g, 3.19 equiv) and 4Å molecular sieve (100 mg) in DCM (20 mL), (3R)-3-methylpiperidin-3-ol (1.0 g, 1.61 equiv) in DCM (5 mL). The mixture was stirred at 0~15 °C for 16 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (4 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum  ether / Ethyl acetate=2 / 1 to 1 / 1) and TLC (PE / EA=1 / 1, Rf=0.49) to afford the tittle compound (1.0 g, 46% yield) as a red solid; LCMS (ESI, M+1): m / z = 374.0. [000182] Step B. (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-bromo-2- chloro-8-fluoro-quinazolin-4-yl)-3-methyl-piperidin-3-ol (400 mg, 1.0 equiv), [(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (512 mg, 3.01 equiv) in dioxane (2.0 mL) were added DIEA (415 mg, 3.01 equiv) and 4Å molecular sieve (80 mg). The mixture was stirred at 95 °C for 42 hours. The mixture was filtered. The filtrate was purified by reversed phase flash [water (FA, 0.1%)] to afford the tittle compound (260 mg, 43% yield) as a red solid; LCMS (ESI, M+1): m / z = 499.2. [000183] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin- 3-ol: A mixture of (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv), 5-ethyl-6- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (96.0 mg, 1.51 equiv) in Methoxycyclopentane (1.0 mL) was degassed and purged with N2 for 3 times, [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (14.6 mg, 0.1 equiv) was added and then the mixture was stirred at 95 °C for 3 hours under N2 atmosphere. After completion, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (4 × 4 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reversed phase flash [C18, 0.1 % formic acid condition] and prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; mobile phase: water(0.225%FA)-ACN; B%: 15%-45% over 10min] to afford the tittle compound (44.1 mg, 35% yield) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.99 (dd, J = 1.6, 8.4 Hz, 1H), 7.65 (dd, J = 6.0, 9.2 Hz, 1H), 7.33 (ddd, J = 2.0, 6.8, 8.8 Hz, 1H), 7.27-7.19 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 5.54-5.37 (m, 1H), 4.58-4.52 (m, 1H), 4.51-4.45 (m, 1H), 4.32 (br d, J = 12.8 Hz, 1H), 4.15 (br d, J = 13.2 Hz, 1H), 3.84-3.68 (m, 1H), 3.53-3.52 (m, 1H), 3.84-3.52 (m, 2H), 3.51-3.42 (m, 1H), 3.28 (br d, J = 4.4 Hz, 1H), 2.65-2.38 (m, 1H), 2.50-2.38 (m, 3H), 2.36- 2.27 (m, 1H), 2.26-2.12 (m, 3H), 2.10-1.99 (m, 1H), 1.90-1.72 (m, 3H), 1.27 (d, J = 13.1 Hz, 3H), 0.82-0.73 (m, 3H). LCMS (ESI, M+1): m / z = 607.4.  [000184] EXAMPLE 35-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione[000185] Step A. 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2-chloro-8-fluoro-4- (2,2,2-trifluoroethoxy)quinazoline (5.00 g, 1.0 equiv) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (2.44 g, 1.1 equiv) in dioxane (50 mL) was added Na2CO3 (4.42 g, 3.0 equiv). The mixture was stirred at 110 °C for 12 hours. The mixture was filtered and washed with EtOAc (10 mL × 2). The organic layer was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under vacuum to afford the title compound (5.30 g, 79% yield) as yellow solid;1H NMR (400 MHz, CDCl3-d) δ = 7.75 (dd, J = 1.6, 8.8 Hz, 1H), 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 5.36 (br d, J = 1.6 Hz, 1H), 5.23 (br d, J = 1.6 Hz, 1H), 4.97 (q, J = 8.4 Hz, 2H), 4.36 - 4.22 (m, 2H), 3.33 - 3.22 (m, 2H), 3.18 (s, 1H), 3.00 (dt, J = 5.6, 9.2 Hz, 1H), 2.30 - 2.24 (m, 1H), 2.19 - 2.09 (m, 2H), 2.02 - 1.91 (m, 3H)  [000186] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol: To a solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (2.00 g, 1.0 equiv) and 5-ethyl-6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.57 g, 1.2 equiv) in CPME (20 mL) was added Cs2CO3 (1.5 M, 8.3 mL, 3.0 equiv) and Ad2nBup-Pd-G3 (604 mg, 0.2 equiv). The mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL × 2). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under vacuum to afford the title compound (1.50 g, 61% yield) as brown solid;1H NMR (400 MHz, CDCl3-d) δ = 7.89 - 7.83 (m, 1H), 7.58 (dd, J = 5.6, 8.8 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.25 - 7.18 (m, 2H), 6.92 (dd, J = 2.4, 15.2 Hz, 1H), 5.44 - 5.19 (m, 1H), 5.02 - 4.84 (m, 2H), 4.40 - 4.30 (m, 2H), 3.36 - 3.23 (m, 2H), 3.07 - 2.96 (m, 1H), 2.51 - 2.09 (m, 6H), 2.03 - 1.87 (m, 4H), 1.27 (t, J = 6.8 Hz, 3H) [000187] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4- c]pyrrole-1,3(2H,3aH)-dione: To a solution of 2,3,3a,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-4,6- dione (35.5 mg, 2.0 equiv) in DMF (0.5 mL) and ACN (0.5 mL) was added K3PO4 (134 mg, 5.0 equiv) and stirred at 25 °C for 0.5 hour. Then 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol (75.0 mg, 1.0 equiv) was added into the reaction solution and stirred at 25 °C for 1.5 hours. The mixture was filtered to remove the insoluble and the filtrate was extracted by DCM (50 mL). The organic layer was concentrated in vacuum. The crude product was purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 um; A: water (NH4HCO3), B: ACN, B%: 40%- 70% over 8 min] to afford the title compound (18.1 mg, 23% yield) as off-white solid;1H NMR (400 MHz, DMSO-d6) δ = 11.38 (br d, J = 5.6 Hz, 1H), 9.92 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.38 - 7.34 (m, 1H), 7.31 (br d, J = 2.8 Hz, 2H), 6.94 (d, J = 2.4 Hz, 1H), 5.36 - 5.21 (m, 1H), 4.43 (br d, J = 11.2 Hz, 2H), 4.21 - 4.15 (m, 2H), 4.11 - 4.00 (m, 2H), 3.68 - 3.64 (m, 2H), 3.10 (br d, J = 12.8 Hz, 2H), 3.02 (br s, 1H), 2.83 (br d, J = 6.0 Hz, 1H), 2.37 - 2.33 (m,  2H), 2.19 - 2.00 (m, 4H), 1.79 (br d, J = 3.6 Hz, 2H), 0.74 - 0.69 (m, 3H); LCMS (ESI, M+1): m / z = 632.3. [000188] EXAMPLE 46-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol[000189] Step A. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2- ol: To a solution of 6-azaspiro[3.5]nonan-2-ol (45.0 mg, 3.0 equiv, HCl) in DMF (0.5 mL) was added K3PO4 (89.7mg, 5.0 equiv). The mixture was stirred at 25 °C for 0.5 hour. Then 5-ethyl- 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv) was added. The mixture was stirred at 40 °C for 2 hours. The mixture was filtered to remove the insoluble. The crude product was purified by prep-HPLC [Phenomenex Synergi Polar-RP 100 × 25 mm × 4 um; A: water (TFA), B: ACN, B%: 31%-51% over 7 min] to afford the title compound (4.19 mg, 7.6% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 10.17 - 9.60 (m, 1H), 7.94 (d, J = 8.4  Hz, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.39 - 7.31 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 5.46 (td, J = 6.8, 17.6 Hz, 1H), 5.36 (br s, 1H), 4.19 - 4.07 (m, 2H), 3.14 - 3.07 (m, 2H), 3.02 (s, 1H), 2.83 (br d, J = 6.0 Hz, 1H), 2.76 (br d, J = 10.8 Hz, 2H), 2.69 - 2.65 (m, 2H), 2.36 - 2.32 (m, 2H), 2.12 - 1.94 (m, 6H), 1.89 - 1.73 (m, 4H), 1.68 - 1.60 (m, 2H), 1.51 - 1.43 (m, 2H), 0.70 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 633.5. [000190] EXAMPLE 57-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one[000191] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a -yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol(50.0 mg, 1.0 equiv) and 1,3,7-triazaspiro[4.5]decan-2-one (15.7 mg, 1.2 equiv) in DMF (0.1 mL) and ACN (0.1 mL) was added K3PO4 (53.8 mg, 3.0 equiv). The mixture was  stirred at 60 °C for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC [Unisil 3-100 C18 Ultra 150 × 50 mm × 3 um; A: water (FA), B: ACN, B%: 15% - 45% over 7 min] and lyophilized. The impurity was further purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 um; A: water (NH4HCO3), B: ACN, B%: 37% - 67% over 8 min] and lyophilized to afford the title compound (3.25 mg, 5.8% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.89 (dd, J = 2.8, 8.8 Hz, 1H), 7.66 (dd, J = 6.0, 9.2 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.27 - 7.18 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 5.51 - 5.27 (m, 1H), 4.50 - 4.27 (m, 2H), 4.02 - 3.81 (m, 4H), 3.42 (ddd, J = 2.8, 9.2, 14.0 Hz, 4H), 3.30 - 3.27 (m, 1H), 3.14 (br dd, J = 1.6, 6.4 Hz, 1H), 2.53 - 2.29 (m, 4H), 2.28 - 2.17 (m, 1H), 2.13 - 1.86 (m, 7H), 0.82 - 0.72 (m, 3H); LCMS (ESI, M+1): m / z = 647.4. [000192] EXAMPLE 67-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione [000193] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7- diazaspiro[4.5]decane-1,3-dione: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol (70.0 mg, 1.0 equiv) and 2,7-diazaspiro[4.5]decane-1,3-dione (36.3 mg, 1.8 equiv) in DMF (0.1 mL) and ACN (0.1 mL) was added K3PO4 (75.4 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was quenched by addition of water (2 mL) and then extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (10mM NH4HCO3), B: ACN, B%: 41%-71% over 8 min] and lyophilized to afford the title compound (10.0 mg, 11% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.83 (br d, J = 8.4 Hz, 1H), 7.70-7.60 (m, 1H), 7.35-7.28 (m, 1H), 7.27-7.18 (m, 2H), 6.95 (s, 1H), 5.41-5.36 (m, 1H), 5.24 (br d, J = 1.2 Hz, 1H), 4.63-4.47 (m, 1H), 4.43-4.33 (m, 1H), 4.30-4.17 (m, 2H), 3.71-3.54 (m, 2H), 3.23 (br s, 2H), 3.08-2.84 (m, 2H), 2.68 (dd, J = 2.0, 18.0 Hz, 1H), 2.56 (br d, J = 5.6 Hz, 3H), 2.29-2.11 (m, 3H), 2.06-1.85 (m, 6H), 1.30 (br dd, J = 1.6, 3.2 Hz, 1H), 0.87-0.66 (m, 3H). LCMS (ESI, M+1): m / z = 660.4. [000194] EXAMPLE 7 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione[000195] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol (150 mg, 1.0 equiv) and 1,3,7-triazaspiro[4.5]decane-2,4-dione (51.5 mg, 1.2 equiv) in DMF (0.5 mL) and ACN (0.5 mL) was added K3PO4 (161 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC [Phenomenex Synergi C18 150 × 25 mm × 10um; A: water (FA), B: ACN, B%: 15%-45% over 10 min] twice to afford the title compound (8.08 mg, 4.5% yield, FA) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 10.83 (br d, J = 1.2 Hz, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.18 (br s, 1H), 7.84 (br dd, J = 3.6, 8.4 Hz, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.27 (m, 3H), 6.96 - 6.90 (m, 1H), 5.40 - 5.16 (m, 1H), 4.30 - 4.17 (m, 2H), 4.14 - 4.07 (m, 1H), 4.05 - 3.98 (m, 1H), 3.46 (br d, J = 13.2 Hz, 2H), 3.36 - 3.33 (m, 1H), 3.09 (br d, J = 12.4 Hz, 2H), 2.86 - 2.78 (m, 1H), 2.38 - 2.31 (m, 2H), 2.15 - 1.97 (m, 5H), 1.91 - 1.74 (m, 5H), 0.71 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 661.3. [000196] EXAMPLE 8  7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide[000197] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol(200 mg, 1.0 equiv) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (70.0 mg, 1.1 equiv) in DMF (0.5 mL) and ACN (0.5 mL) was added K3PO4 (215 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC [Phenomenex Synergi C18 150 × 25 mm × 10um; A: water (FA), B: ACN, B%: 16%-46% over 10 min] twice to afford the title compound (16.39 mg, 6.7% yield) as light yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.92 (br s, 1H), 7.85 (dd, J = 8.8, 13.6 Hz, 1H), 7.76 (dd, J = 6.4, 8.4 Hz, 1H), 7.38 - 7.26 (m, 4H), 7.24 - 7.13 (m, 1H), 6.92 (s, 1H), 5.43 - 5.12 (m, 1H), 4.15 - 3.93 (m, 3H), 3.87 - 3.75 (m, 1H), 3.73 - 3.43 (m, 2H), 3.32 - 3.27 (m, 1H), 3.14 - 3.06 (m, 3H), 3.01 (br s, 1H), 2.88 - 2.77 (m, 1H),  2.42 - 2.31 (m, 2H), 2.13 (br s, 1H), 2.08 - 1.96 (m, 3H), 1.90 - 1.74 (m, 6H), 0.71 (dt, J = 2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 683.3. [000198] EXAMPLE 95-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000199] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-ethyl-6-fluoro-4- (8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol(55.0 mg, 1.0 equiv) and N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (23.2 mg, 1.2 equiv) in DMF (0.1 mL) and ACN(0.1 mL) was added K3PO4 (59.2 mg, 3.0 equiv). The mixture was stirred at 60 °C for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3).  The organic layers were dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC [Unisil 3-100 C18 Ultra 150 × 50 mm × 3 um; A: water (FA), B: ACN, B%: 17% - 47% over 7 min] twice to afford the title compound (3.80 mg, 5.7% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.95 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 5.6, 9.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.27 - 7.19 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.71 (s, 1H), 5.45 - 5.27 (m, 1H), 5.24 - 5.10 (m, 2H), 4.56 - 4.50 (m, 2H), 4.45 - 4.24 (m, 4H), 3.52 - 3.33 (m, 6H), 3.14 - 3.06 (m, 4H), 2.49 - 2.31 (m, 5H), 2.29 - 2.14 (m, 2H), 2.12 - 1.89 (m, 3H), 0.76 (t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z = 700.3. [000200] EXAMPLE 10(3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol [000201] Step A. (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin- 3-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoro-quinazoline (300 mg, 1 equiv) and 4Å MS (1.5 mg) in DCM (0.5 mL) was added DIEA (370 mg, 3 equiv) and (R)-3-methylpiperidin-3- ol (132 mg, 1.2 equiv). The mixture was stirred at 0 °C for 0.5 hr. After completion, the residue was extracted with DCM (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC( 0.1% FA condition) to afford the title compound (170 mg, 45% yield) as yellow solid. LCMS (ESI, M+1, M+3): m / z =391.9, 393.9. [000202] Step B. (R)-1-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)- 6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-bromo-2-chloro- 6,8-difluoro-quinazolin-4-yl)-3-methyl-piperidin-3-ol (165 mg, 1 equiv) and 4Å MS (1.5 mg) in dioxane (1 mL) was added DIEA (217 mg, 4 equiv) and (1- ((dimethylamino)methyl)cyclopropyl)methanol (271 mg, 5 equiv). The mixture was stirred at 90 °C for 48 hrs. After completion, the reaction mixture was filtered and purified by reversed-phase HPLC ( 0.1% FA condition) to afford the title compound (67 mg, 33% yield) as yellow oil. LCMS (ESI, M+1, M+3): m / z = 484.9, 486.9. [000203] Step C. (3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8- difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (62 mg, 1 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (69.3 mg, 2 equiv), methanesulfonato(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (7.98 mg, 0.1 equiv) and Cs2CO3 (107= mg, 3 equiv) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 hours under N2 atmosphere. After completion, the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 × 30mm × 5μm;mobile phase: [water(FA)-ACN];B%: 17%-47%,8min) to afford the title compound (18.4 mg, 26% yield) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.88 - 7.77 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.33 - 7.20 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.43 - 4.34 (m, 2H), 4.32 - 4.21 (m,  1H), 4.08 (br d, J = 13.6 Hz, 1H), 3.54 - 3.42 (m, 1H), 3.42 - 3.35 (m, 1H), 2.86 (br s, 2H), 2.69 - 2.50 (m, 7H), 2.49 - 2.41 (m, 1H), 2.20 - 2.09 (m, 1H), 1.88 - 1.71 (m, 3H), 1.28 (d, J = 11.2 Hz, 3H), 0.88 - 0.76 (m, 5H), 0.73 - 0.61 (m, 2H); LCMS (ESI, M+1): m / z = 595.3. [000204] EXAMPLE 11(R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((R)-8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol [000205] EXAMPLE 12(R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((S)-8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol [000206] Step A. (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((R)-8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: (3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (35.0 mg, 1 equiv) was purified with SFC [column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: 0.1%NH3•H2O in IPA; B%: 45%-45%, 3.3 minutes] (tR: 2.232 min) and prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN]; B%: 20%-50%, 2minutes] to afford two peaks. [000207] Peak 1 (Example 11) (35.0 mg, 1 equiv) was purified by SFC [column: DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 μm); mobile phase: 0.1%NH3•H2O in IPA; B%: 45%- 45%, 3.3 minutes] (tR: 1.944 min) and prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN]; B%: 20%-50%, 2minutes] to afford the tittle compound (6.74 mg, 18% yield, 0.22FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.83 (dd, J = 1.6, 10.0 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 4.38 (s, 2H), 4.24 (br d, J = 13.6 Hz, 1H), 4.07 (br d, J = 13.2 Hz, 1H), 3.48-3.34 (m, 2H), 2.79 (br s, 2H), 2.57 (br s, 6H), 2.53-2.31 (m, 2H), 2.24-2.07 (m, 1H), 1.91- 1.69 (m, 3H), 1.29 (s, 3H), 0.90-0.75 (m, 5H), 0.65 (br s, 2H); LCMS (ESI, M+1): m / z = 595.4; HPLC: >99 % ee, column: Chiralpak AD-350 × 4.6 mm I.D., 3 µm, mobile phase: phase A for CO2, and phase B for IPA (0.05%DEA), gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min, detector: 220 nm, tR: 1.942 min. [000208] Peak 2 (Example 12) (13.5 mg, 36% yield, 0.4FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.80 (br d, J = 9.6 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 4.44-4.33 (m, 2H), 4.27 (br d, J = 12.8 Hz, 1H), 4.07 (br d, J = 13.2 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 3.45-3.35 (m, 1H), 2.89-2.70 (m, 2H), 2.67-2.53 (m, 6H), 2.53-2.32 (m, 2H), 2.23-2.08 (m, 1H), 1.91-1.68 (m, 3H), 1.26 (s, 3H), 0.90-0.74 (m, 5H), 0.66 (br s, 2H); LCMS (ESI, M+1): m / z = 595.4; HPLC: 99 % ee, column: Chiralpak AD-350 × 4.6 mm I.D., 3 µm, mobile phase: phase A for CO2, and phase B for IPA (0.05%DEA), gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min, detector: 220 nm, tR: 2.227 min. [000209] EXAMPLE 13  (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000210] Step A. (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin- 3-ol: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (2 g, 1.0 equiv), 4Å MS (600 mg) and DIPEA (3.29 g, 4.4 mL, 4.0 equiv) in DCM (20 mL) was added (R)-3-methylpiperidin- 3-ol (660 mg, 0.9 equiv) in DCM (3 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. The mixture was filtered and diluted with water (30 mL), extracted with DCM (3 × 30 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by reversed phase flash [C18, 0.1% formic acid condition] to afford the title compound (1.4 g, 55% yield) as yellow solid; LCMS [ESI, M+3]: m / z = 393.7. [000211] Step B. (R)-1-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7- bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (230 mg, 1.0 equiv) and  ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (102 mg, 1.1 equiv) in dioxane (2 mL) were added DIPEA (227 mg, 306 μL, 1.1 equiv) and 4Å MS (50 mg). The mixture was stirred at 100 °C for 72 hours. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (4 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by reversed phase flash [C18, 0.1% formic acid condition] to afford the title compound (86 mg, 27% yield) as yellow solid; LCMS [ESI, M+3]: m / z = 517.2. [000212] Step C. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin- 3-ol: A mixture of (R)-1-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (70.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (85.9 mg, 2.0 equiv) and Ad2nBuP- Pd-G3 (9.89 mg, 0.1 equiv), Cs2CO3 (1.5 M, 272 μL, 3.0 equiv) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 2 hours under N2 atmosphere. The mixture was filtered, diluted with water (10 mL) and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated. The residue was purified by reversed phase flash [C18, 0.1% formic acid condition] and prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 50% - 80% over 10 minutes] to afford the title compound (11 mg, 12% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.80-7.77 (m, 1H), 7.67 (dd, J = 5.6, 9.2 Hz, 1H), 7.31-7.21 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 5.39-5.23 (m 1H), 4.63-4.59 (m, 1H), 4.35-4.18 (m, 3H), 4.05 (br d, J = 13.2 Hz, 1H), 3.55-3.37 (m, 2H), 3.24-3.17 (m, 2H), 3.08-2.95 (m, 1H), 2.62-2.50 (m, 1H), 2.49-2.26 (m, 2H), 2.25-2.10 (m, 3H), 2.03-1.70 (m, 6H), 1.27 (d, J = 12.0 Hz, 3H), 0.81 (q, J = 7.2 Hz, 3H); SFC [Column: Chiralpak AD-350 × 4.6 mm I.D, 3 μm Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution IPA (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar]; LCMS (ESI, M+1): m / z = 625.3. [000213] EXAMPLE 14  (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol[000214] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol: A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol (150 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (156 mg, 5.0 equiv) and DIEA (371 mg, 11.7 equiv), 4 Å molecular sieve (10 mg) in DMF (1 mL) was stirred at 40 °C - 60 °C for 72 hours. After completion, the mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 20%- 50%,10min) and (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(NH3H2O)- ACN];B%: 45%-75%,8min) to afford the title compound (7.57 mg, 4.8% yield) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.04-7.96 (m, 1H), 7.69 (dd, J = 5.6, 8.8 Hz, 1H), 7.33- 7.20 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 5.44-5.22 (m, 1H), 4.77-4.67 (m, 1H), 4.61 (br d, J = 11.2 Hz, 1H), 4.41-4.34 (m, 1H), 4.32 (d, J = 10.4 Hz, 1H), 4.25-4.19 (m, 1H), 3.63-3.55 (m, 1H), 3.47 (br d, J = 12.4 Hz, 1H), 3.40-3.35 (m, 1H), 3.30-3.14 (m, 3H), 3.09-2.99 (m, 1H), 2.66-2.53 (m,  1H), 2.48-2.41 (m, 1H), 2.38 (br d, J = 4.0 Hz, 1H), 2.28 (br s, 1H), 2.27-2.24 (m, 1H), 2.24-2.14 (m, 2H), 2.08-1.97 (m, 2H), 1.96-1.81 (m, 3H), 1.60-1.45 (m, 1H), 0.87-0.78 (m, 3H). LCMS (ESI, M+1): m / z = 637.3. [000215] EXAMPLE 15(6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol[000216] Step A. (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol: A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv), (S)-6-methyl-1,4-oxazepan-6-ol (226 mg, 7.0 equiv) and DIEA (191 mg, 6.0 equiv), 4Å molecular sieve (10.0 mg) in DMF (1 mL) was stirred at 80°C for 72 hrs. After completion, the mixture is filtered and purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA) - ACN];B%: 20% - 50%,10 min) to afford the title compound (16.1 mg, 9% yield) as off-white solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.25-8.07 (m, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.31-7.21 (m, 2H), 6.98 (dd, J = 2.4, 8.8 Hz, 1H), 5.54-5.32 (m, 1H), 4.55-4.37 (m, 4H), 4.13-3.97 (m, 2H), 3.94-3.82 (m, 2H), 3.75-3.56 (m, 3H), 3.50 (br dd,  J = 7.2, 9.6 Hz, 2H), 3.23-3.16 (m, 1H), 2.61-2.33 (m, 4H), 2.29-2.21 (m, 1H), 2.18-2.08 (m, 2H), 2.04-1.93 (m, 1H), 1.26 (d, J = 8.4 Hz, 3H), 0.84-0.71 (m, 3H); LCMS (ESI, M+1): m / z = 641.1. [000217] EXAMPLE 165-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)- dione[000218] Step A. (3aR,6aS)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: A mixture of 4-(6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv), (3aR,6aS)- tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (161 mg, 7.0 equiv) and 4Å molecular sieve (5 mg) in DIEA (1 mL) and DMF (0.5 mL) was stirred at 80°C for 48 hrs. After completion, the mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water( NH4HCO3) - ACN];B%: 35%-65%,8min) and prep-HPLC (column:  Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA) - ACN];B%: 18%- 48%,10min). The desired fractions were collected and lyophilization. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA) - ACN];B%: 18%-48%,10min ) to afford the title compound (6.27 mg, 5% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.88 (br d, J = 10.0 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.34-7.18 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 5.53-5.33 (m, 1H), 4.66 (br d, J = 12.0 Hz, 2H), 4.52-4.36 (m, 2H), 4.28-4.08 (m, 2H), 3.69 (br d, J = 7.6 Hz, 2H), 3.73-3.45 (m, 2H), 3.26-3.18 (m, 1H), 2.59-2.33 (m, 4H), 2.31-2.24 (m, 1H), 2.22-2.11 (m, 2H), 2.08-1.99 (m, 1H), 0.79 (br t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z = 650.1. [000219] EXAMPLE 176-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one[000220] Step A. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,6- diazaspiro[3.5]nonan-2-one: [000221] A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1 equiv) 1,6-diazaspiro[3.5]nonan-2-one (68.9 mg, 2 equiv), DIEA (191 mg, 6 equiv) in DMF (1  mL) was stirred 40 °C for 12 hours. After completion, the mixture was purified by prep-HPLC Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 20%-50%,10min to afford the title compound (53.8 mg, 33% yield) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.75-7.60 (m, 2H), 7.35-7.19 (m, 2H), 6.98 (s, 1H), 5.55-5.30 (m, 1H), 4.55- 4.37 (m, 2H), 4.22-4.07 (m, 2H), 3.91-3.77 (m, 1H), 3.74-3.53 (m, 4H), 2.90-2.71 (m, 2H), 2.61- 2.35 (m, 4H), 2.33-2.26 (m, 1H), 2.22-1.86 (m, 8H), 0.80 (br t, J = 7.2 Hz, 3H). LCMS (ESI, M+1): m / z = 650.6. [000222] EXAMPLE 18(2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol [000223] EXAMPLE 19(2R,4r)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol  [000224] Step A. 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 2,2,2-trifluoroethanol (2.39 g, 1.0 equiv) in THF (80 mL) was added NaH (1.05 g, 1.1 equiv) at 0 °C. After completion, the mixture was stirred at 10 °C for 0.5 hour and the mixture was added to a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (7.5 g, 1.0 equiv) in THF (80 mL) with stirred at -40 °C. The mixture was stirred at -40 °C for 1 hour and 25 °C for 2 hours. The reaction mixture was quenched by addition of H2O (100 mL) at 0 °C and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash [C18, water (FA, 0.1%) / acetonitrile] to afford the title compound (5 g, 54.3% yield) as yellow solid. LCMS (ESI, M+1, M+3): m / z = 376.7, 378.7. [000225] Step B. 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a mixture of 7-bromo-2-chloro-6,8- difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (4.9 g, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methanol (5.37 g, 2.6 equiv) in THF (50 mL) was added Na2CO3 (4.13 g, 3.0 equiv). The mixture was stirred at 40 °C for 24 hours and 60 °C for another 16 hours. After completion, the mixture was filtered to remove Na2CO3. The residue was diluted with water (100 ml) and extracted with ethyl acetate (50 ml × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 × 50mm × 10 um;mobile phase: [water(FA)- ACN];B%: 25%-55%,30min) to afford the title compound (3.3 g, 50% yield) as white solid. LCMS (ESI, M+1, M+3): m / z = 499.9, 501.9.  [000226] Step C. 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(2,2,2-trifluoroethoxy)quinazoline (3.3 g, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (2.50 g, 1.2 equiv) in methoxycyclopentane (35 mL) was added Cs2CO3 (1.5 M, 3.0 equiv) at 25 °C. The suspension was degassed under vacuum and purged with N2 two times. Methanesulfonato(diadamantyl-n-butylphosphino)-2- amino-1,1-biphenyl-2-yl)palladium(II) (480 mg, 0.1 equiv) was added, the suspension was degassed under vacuum and purged with N2 three times. The mixture was stirred at 90 °C for 2 hours. After completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 × 50mm × 10 um; mobile phase: [water (FA)-ACN]; B%: 20%-50%,22min) to afford the title compound (2.9 g, 71.4% yield) as white solid. LCMS (ESI, M+1): m / z = 610.5. [000227] Step D. (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6- azaspiro[3.5]nonan-2-ol and Trans-(2R,4r)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6- azaspiro[3.5]nonan-2-ol: A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol (100 mg, 1.0 equiv) , 6-azaspiro[3.5]nonan-2-ol (43.7 mg, 1.5 equiv, HCl) , 4Å molecular sieve (50.0 mg, 1.0 equiv ), K3PO4 (104 mg, 3.0 equiv) in DMF (0.5 mL) and ACN (0.5 mL) were degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 12 hours under N2 atmosphere. After completion, the mixture was filtered. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added, and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and was purified by prep-TLC (SiO2, Dichloromethane / Methanol=10 / 1 column: Phenomenex Luna C18150 × 25mm × 10um; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 10min) to afford two peaks.  [000228] Example 18 (25.1 mg, 46.5% yield) as white solid:1H NMR (400 MHz, CD3OD) δ= 8.53 (br s, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (br d, J = 10.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.46 - 5.22 (m, 1H), 4.41 - 4.21 (m, 3H), 3.88 (s, 2H), 3.85 - 3.74 (m, 2H), 3.41 (br d, J = 2.0 Hz, 3H), 3.14 - 2.99 (m, 1H), 2.66 - 2.51 (m, 1H), 2.48 - 2.25 (m, 3H), 2.25 - 2.14 (m, 3H), 2.11 - 1.99 (m, 2H), 1.98 - 1.90 (m, 1H), 1.89 - 1.68 (m, 6H), 0.81 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =651.4. [000229] Example 19 (10.3 mg, 18.7% yield) as white solid:1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (br s, 1H), 7.68 (dd, J = 5.8, 9.2 Hz, 1H), 7.60 (br d, J = 9.8 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.54 - 5.20 (m, 1H), 4.43 - 4.29 (m, 2H), 4.24 (br t, J = 7.3 Hz, 1H), 3.97 - 3.73 (m, 4H), 3.53 - 3.35 (m, 3H), 3.17 - 3.02 (m, 1H), 2.66 - 2.52 (m, 1H), 2.50 - 2.37 (m, 2H), 2.36 - 2.28 (m, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.02 (m, 2H), 2.01 - 1.90 (m, 1H), 1.80 (br s, 4H), 1.69 (td, J = 7.3, 11.7 Hz, 2H), 0.81 (br t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z =651.4 [000230] EXAMPLE 207-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one [000231] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decan-2-one: To a mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol (150 mg, 1.0 equiv), 1,3,7-triazaspiro[4.5]decan-2-one (76.4 mg, 2.0 equiv) in DMF (0.2 mL) was added DIEA (318 mg, 10 equiv) and 4 Å molecular sieve (10 mg). The mixture was stirred at 60 °C for 12 hours. After completion, the mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 18%- 48%,10min) and (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(NH3H2O)- ACN];B%: 30%-60%,8min) to afford the title compound (16.7 mg, 10% yield) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.74-7.57 (m, 2H), 7.36-7.12 (m, 2H), 6.98 (br s, 1H), 5.44-5.20 (m, 1H), 4.37-4.17 (m, 2H), 3.95-3.73 (m, 4H), 3.43 (ddd, J = 2.4, 6.8, 9.2 Hz, 1H), 3.30-3.13 (m, 4H), 3.06-2.95 (m, 1H), 2.60-2.11 (m, 4H), 2.06-1.84 (m, 7H), 0.88-0.71 (m, 3H). LCMS (ESI, M+1): m / z = 665.2. [000232] EXAMPLE 217-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione  [000233] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione: To a solution of 4-(6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv) and 1,3,9-triazaspiro[4.5]decane-2,4-dione (55.51 mg, 2.0 equiv) in DMF (0.5 mL) was added 4Å MS (20 mg) and DIEA (63.6 mg, 3.0 equiv). The mixture was stirred at 40 °C for 24 hours. The reaction mixture was filtered and purified by prep-HPLC [column: Phenomenex C1875 × 30 mm × 3 µm;mobile phase: (water(FA)-ACN];B%: 18%-48%,7min] to afford the title compound (32.7 mg, 29% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.77-7.66 (m, 2H), 7.36-7.22 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 5.56- 5.35 (m, 1H), 4.56-4.31 (m, 4H), 3.74-3.49 (m, 5H), 3.30-3.21 (m, 1H), 2.64-2.37 (m, 4H), 2.35- 2.15 (m, 4H), 2.12-1.94 (m, 4H), 0.88-0.76 (m, 3H)); LCMS (ESI, M+1): m / z = 679.6. [000234] EXAMPLE 22 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide[000235] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide: To a solution of 4-(6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol (150 mg, 1 equiv) in DMF (1.5 mL) were added DIEA (254 mg, 8 equiv), 4Å molecular sieve (5 mg) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (94.1 mg, 2 equiv). The mixture was stirred at 40 °C for 72 hours. After completion, the mixture was filtered and purified by (column: Phenomenex luna C18150 × 25mm × 10µm; mobile phase: [water(FA)- ACN];B%: 20%-50%,10min) to afford the title compound (9.9 mg, 5.4% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.57 - 8.46 (m, 1H), 7.74 - 7.64 (m, 2H), 7.29 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.00 - 6.94 (m, 1H), 5.51 - 5.32 (m, 1H), 4.51 - 4.28 (m, 3H), 4.25 - 4.14 (m, 1H), 3.75 - 3.45 (m, 5H), 3.42 (br d, J = 11.6 Hz, 1H), 3.25 - 3.17 (m, 2H), 2.63 - 2.33 (m, 4H), 2.32 - 2.22 (m, 1H), 2.17 - 1.98 (m, 5H), 1.95 - 1.81 (m, 2H), 0.81 (br t, J = 7.2 Hz, 3H). LCMS (ESI, M+1): m / z = 701.3. [000236] EXAMPLE 23 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000237] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 4-(6,8- difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv) in DMF (1.5 mL) was added DIEA (254 mg, 8.0 equiv), 4 Å molecular sieve (5 mg) and N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (102 mg, 2.0 equiv). The mixture was stirred at 40 °C for 72 hrs. After completion, the mixture was filtered and purified by (column: Phenomenex luna C18 150 × 25mm × 10µm;mobile phase: [water(FA)-ACN];B%: 22%- 52%,10min) and prep-HPLC (column: Welch Xtimate C18150 × 25mm × 5µm;mobile phase: [water(NH3H2O)-ACN];B%: 32%-62%,8min) to afford the title compound (12.9 mg, 7.1% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.84 - 7.63 (m, 2H), 7.35 - 7.20 (m, 2H), 6.98 (br s, 1H), 6.71 (s, 1H), 5.56 - 5.31 (m, 1H), 5.24 - 5.06 (m, 2H), 4.61 - 4.28 (m, 6H), 3.70 - 3.45 (m, 3H), 3.35 (s, 3H), 3.03 (s, 4H), 2.71 - 2.48 (m, 2H), 2.46 - 2.24 (m, 5H), 2.22 - 1.96 (m, 3H), 0.80 (br t, J = 6.8 Hz, 3H); LCMS(ESI, M+1): m / z = 718.3. [000238] EXAMPLE 24  (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000239] Step A. (R)-1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin- 3-ol：To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (723 mg, 1.0 equiv) and DIEA (1.41 g, 5.0 equiv), 4Å MS (100 mg) in DCM (10 mL) was added (R)-3-methylpiperidin-3- ol (302 mg, 1.2 equiv) in DCM (1 mL) dropwise at 0 °C. The reaction was stirred at 0~15°C for 0.5 hour. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 1 / 1) to give the title compound (541 mg, 59% yield, 98.7% purity) as yellow solid; LCMS (ESI, M+1): m / z = 409.9. [000240] Step B. (R)-1-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol：To a mixture of (R)-1-(7- bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (478 mg, 1.0 equiv), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (558 mg, 3.0 equiv), 4Å molecular sieve (50 mg) in dioxane (10 mL) was added DIEA (755 mg, 5.0 equiv). The reaction was stirred at 90 °C for 16 hours. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with Ethyl acetate (10 mL). The combined organic layer was dried over Na2SO4, filtered  and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase flash (0.1% FA condition) to afford the title compound (214 mg, 32% yield, 93.0% purity) as light yellow solid; LCMS (ESI, M+1): m / z = 533.1. [000241] Step C. (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol: To a mixture of (R)-1-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (71.3 mg, 1.2 equiv), K2CO3 (77.9 mg, 3.0 equiv) in dioxane (1.5 mL) and H2O (0.5 mL) was added RuPhos Pd G3 (15.7 mg, 0.1 equiv) and RuPhos (8.77 mg, 0.1 equiv) under N2. The reaction was stirred at 80 °C for 1.5 hours. After completion, the reaction mixture was diluted with H2O (2 mL) and extracted with Ethyl acetate (4 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase flash (0.1% FA condition) and prep-HPLC (Phenomenex Synergi C18 150 × 25 mm × 10 µm; A: water (0.225%FA), B: ACN, B%: 19% - 49% over 10 min) to afford the title compound (4.42 mg, 3% yield) as white solid;1H NMR (400 MHz, methanol-d4): δ = 8.57 - 8.48 (m, 1H), 8.17 - 8.09 (m, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 5.47 - 5.29 (m, 1H), 4.60 (br s, 1H), 4.45 - 4.38 (m, 1H), 4.36 - 4.31 (m, 1H), 4.10 (br d, J = 14.0 Hz, 1H), 3.57 (d, J = 13.2 Hz, 1H), 3.52 - 3.34 (m, 4H), 3.18 - 3.10 (m, 1H), 2.68 - 2.54 (m, 1H), 2.52 - 2.04 (m, 7H), 2.01 - 1.92 (m, 1H), 1.88 - 1.71 (m, 3H), 1.32 - 1.25 (m, 3H), 0.84 - 0.74 (m, 3H); LCMS (ESI, M+1): m / z = 641.2. [000242] EXAMPLE 25  5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000243] Step A. 5-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4,6- trichloro-8-fluoro-quinazoline (400 mg, 1.0 equiv) in DCM (4 mL) was added DIEA (782 mg, 5.0 equiv) at 0 °C. The mixture was added N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (385 mg, 1.3 equiv, HCl) and stirred at 25 °C for 0.5 hour. The reaction mixture was extracted with dichloromethane (2 × 10 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (515 mg, crude) as white solid. LCMS (ESI, M+1): m / z = 503.1. [000244] Step B. 5-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-2,6-dichloro-8-fluoro- quinazolin-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (515 mg, 1.0 equiv) in dioxane (5 mL) was added DIEA (398 mg, 3.0 equiv) and [(2R,8S)-2-  fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (816 mg, 5.0 equiv). The mixture was stirred at 90 °C for 36 hours. The reaction mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (301 mg, 46% yield) as yellow solid; LCMS (ESI, M+1): m / z = 625.8. [000245] Step C. 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of 5-(7-bromo-6- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (300 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (273 mg, 1.8 equiv), RuPhos Pd G3 (40.2 mg, 0.1 equiv), RuPhos (67.21 mg, 0.3 equiv), Cs2CO3 (469 mg, 3.0 equiv) in dioxane (3 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 6 hours under N2 atmosphere. The reaction mixture was extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated. The residue was purified by prep-HPLC [Unisil 150 × 50 mm × 3 um; A: water (FA), B: ACN; B%: 15%-45% over 10min] to afford the title compound (100 mg, 27% yield, 0.7FA) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.09 (s, 1H), 7.70-6.65 (m, 1H), 7.31-7.21 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.74 (s, 1H), 5.48-5.30 (m, 1H), 5.21-5.06 (m, 2H), 4.57-4.50 (m, 2H), 4.43-4.27 (m, 4H), 3.60-3.41 (m, 3H), 3.35 (s, 3H), 3.19-3.13 (m, 1H), 3.08 (s, 3H), 2.67- 2.57 (m, 1H), 2.51-2.31 (m, 4H), 2.29-2.21 (m, 2H), 2.16-2.06 (m, 2H), 2.05-1.93 (m, 1H), 0.78 (dt, J = 2.0, 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 734.2. [000246] EXAMPLE 26 (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol[000247] Step A. (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv), (3R)-3- methylpiperidin-3-ol (41.0 mg, 2.0 equiv) and 4Å molecular sieve (10 mg) in DMF (1 mL) was added DIEA (69.0 mg, 3.0 equiv). The mixture was stirred at 60 °C for 24 hours. The mixture was filtered and washed with DMF (1 mL). The residue was purified by prep-HPLC [Phenomenex C18 75 × 30 mm × 3 µm; A: water (FA), B: ACN, B%: 18%-48% over 7 min] to afford the title compound (58.4 mg, 56% yield) as yellow solid; SFC: Rt = 0.992 min, 1.715 min; (column: Chiralpak IC-350×4.6mm I.D., 3um; mobile phase: phase A for CO2, and phase B for MeOH (0.05% DEA); gradient elution: 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temp: 35 °C; back pressure: 100 Bar).1H NMR (400 MHz, methanol-d4) δ = 7.97 (d, J = 8.6 Hz, 1H), 7.65 (dd, J = 6.0, 9.2 Hz, 1H), 7.31 (dd, J = 7.2, 8.4 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.95 (d, J = 1.6 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.28 (br d, J = 12.0 Hz, 1H), 4.12 (br d, J = 13.2 Hz, 1H), 3.63 - 3.40 (m, 2H), 3.15 - 2.98 (m, 2H), 2.78 (s, 6H), 2.45 (dt, J = 3.2, 7.2 Hz, 2H), 2.23 - 2.06 (m, 1H), 1.89 - 1.71 (m, 3H), 1.27 (d, J = 12.8 Hz, 3H), 0.94 - 0.85 (m, 2H), 0.82 - 0.72 (m, 5H); LCMS (ESI, M+1): m / z = 577.3. [000248] EXAMPLE 27  4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000249] Step A.7-bromo-2-chloro-8-fluoro-6-iodo-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-quinazoline (9.20 g, 1.0 equiv) and DIEA (8.46 g, 3.0 equiv) in THF (80 mL) was added dropwise N-methylmethanamine (2 M, 21.8 mL, 2.0 equiv). The mixture was stirred at -40 °C for 0.5 hour. The reaction mixture was dissolved in DCM (700 mL). The mixture was diluted with water (10 mL) and extracted with DCM (30 mL × 3). The organic layers were dried with anhydrous sodium sulfate, concentrated and triturated with MTBE (100 mL) at 20 °C for 20 mins to afford the title compound (8.00 g, 85% yield) as yellow solid. [000250] Step B. 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-6-iodo-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2-chloro-8- fluoro-6-iodo-N,N-dimethyl-quinazolin-4-amine (8.00 g, 1.0 equiv), ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (8.88 g, 3.0 equiv) in dioxane (40 mL) was added DIEA (7.21 g, 3.0 equiv). The mixture was stirred at 100 °C for 96 hours. The reaction mixture was poured into water (200 mL) to form a solid. The solid was filtered and the filtered  cake was triturated with PE (200 mL) at 20 °C for 1 hour to afford the title compound (7.70 g, 66% yield) as yellow solid; LCMS (ESI, M+3): m / z = 554.9. [000251] Step C. 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine: To a solution of 7-bromo-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-iodo-N,N-dimethylquinazolin-4- amine (1.00 g, 1.0 equiv) in dioxane (10 mL) and H2O (1 mL) was added 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (334 mg, 1.2 equiv), K2CO3 (749 mg, 3.0 equiv), Pd(dppf)Cl2 (13.2 mg, 0.01 equiv) and degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 16 hours under N2 atmosphere. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by reversed phase flash [C18, 0.1% formic acid] to afford the title compound (300 mg, 35% yield) as yellow solid; LCMS (ESI, M+3): m / z = 455.0. [000252] Step D. 4-(4-(dimethylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine (1.80 g, 1.0 equiv) and 5-ethyl-6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.37 g, 1.2 equiv) in methoxycyclopentane (18 mL) was added Ad2nBuP-Pd-G3 (393 mg, 0.15 equiv) and Cs2CO3 (326 mg, 3 equiv). The mixture was stirred at 90 °C for 12 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product purified by prep-HPLC [Phenomenex luna C18150 × 40mm × 5 µm; A: water (FA), B:ACN; B%: 20%-50% over 10min) to afford the title compound (475 mg, 21% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.58-8.46 (m, 1H), 8.26 (s, 1H), 7.77-7.60 (m, 1H), 7.32-7.16 (m, 2H), 6.93- 6.80 (m, 1H), 6.37-6.17 (m, 1H), 5.78-5.60 (m, 1H), 5.53-5.27 (m, 1H), 5.19-5.05 (m, 1H), 4.86 (s, 9H), 4.53-4.34 (m, 2H), 3.73-3.56 (m, 1H), 3.55 (s, 6H), 3.44 (s, 2H), 3.24-3.16 (m, 1H), 2.59- 2.34 (m, 3H), 2.31-2.20 (m, 2H), 2.19-2.09 (m, 2H), 2.05-1.95 (m, 1H), 0.81-0.67 (m, 3H); LCMS (ESI, M+1): m / z = 563.2. [000253] EXAMPLE 28  4-(dimethylamino)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-ol[000254] Step A. 7-bromo-2,6-dichloro-8-fluoro-N,N-dimethyl-quinazolin-4-amine: To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (5.1 g, 1.0 equiv) in THF (50 mL) was added DIEA (5.99 g, 8.07 mL, 3.0 equiv) and N-methylmethanamine (2 M, 23.16 mL, 3.0 equiv). The mixture was stirred at -40 °C for 0.5 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 50 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by slurried by acetonitrile (20 mL) at 25 °C for 0.5 hour afford the title compound (6.2 g, 88% yield) as white solid; LCMS (ESI, M+1): m / z = 339.8. [000255] Step B. 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-N,N-dimethylquinazolin-4-amine: To a mixture of 7-bromo-2,6- dichloro-8-fluoro-N,N-dimethyl-quinazolin-4-amine (6.2 g, 1.0 equiv) was added ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14.6 g, 5.0 equiv). The mixture was stirred at 90 °C for 24 hours. The mixture was filtered. The crude product was purified by re-crystallization from acetonitrile afford the title compound (4.1 g, 48% yield) as white solid; LCMS (ESI, M+1): m / z = 462.9.  [000256] Step C. 6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N,N- dimethylquinazolin-4-amine: A mixture of 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,N-dimethylquinazolin-4-amine (4.3 g, 1.0 equiv), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (5.03 g, 1.5 equiv), RuPhos-Pd-G3 (778.89 mg, 0.1 equiv), RuPhos (1.30 g, 0.3 equiv) and Cs2CO3 (9.10 g, 3.0 equiv) in dioxane (32 mL) and H2O (8 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N2 atmosphere. The mixture was poured into water (10 mL) and filtered. The filtrate was extracted with ethyl acetate (4 × 30 mL). The organic phase was dried over Na2SO4and concentrated under vacuum. The crude product was purified with reversed phase flash [C18, 0.1% formic acid] afford the title compound (1.6 g, 28% yield) as yellow solid; LCMS (ESI, M+1): m / z = 615.3. [000257] Step D. 4-(dimethylamino)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6- ol: A mixture of 6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4- amine (640 mg, 1.0 equiv), Pd2(dba)3 (95.3 mg, 0.1 equiv), t-Bu Xphos (88.4 mg, 0.2 equiv) and KOH (175 mg, 3.0 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (4 × 5 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with reversed phase flash [C18, 0.1% formic acid] afford the title compound (120 mg, 19% yield) as yellow solid; LCMS (ESI, M+1): m / z = 597.3. [000258] Step E. 4-(dimethylamino)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-ol : To a solution of 4-(dimethylamino)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-ol (35 mg, 1.0 equiv) in ACN (1 mL) was added HCl•dioxane (4 M, 1 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was purified with prep-HPLC [Phenomenex luna C18 150 × 25 mm × 10 um; A:  water(FA); B: ACN; B%: 14% -34% over 2min] afford the title compound (120 mg, 19% yield) as light yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.65-7.61 (m, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.28-7.16 (m, 2H), 6.92 (d, J = 2.4 Hz, 1H), 5.34 (s, 1H), 4.52-4.37 (m, 2H), 3.73- 3.53 (m, 3H), 3.53-3.41 (m, 6H), 3.24 (d, J = 5.6 Hz, 1H), 2.60-2.37 (m, 4H), 2.35-2.25 (m, 1H), 2.21-2.10 (m, 2H), 2.01 (d, J = 4.4 Hz, 1H), 0.85-0.77 (m, 3H); LCMS (ESI, M+1): m / z = 553.4. [000259] EXAMPLE 294-(6-cyclopropyl-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000260] Step A. 7-bromo-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine: A mixture of 7-bromo-8- fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-iodo-N,N- dimethylquinazolin-4-amine (500 mg, 1.0 equiv), cyclopropylboronic acid (233 mg, 3.0 equiv), Pd(dppf)Cl2 (66.1 mg, 0.1 equiv), K3PO4 (1.5 M, 1.8 mL, 3.0 equiv) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over Na2SO4and concentrated under vacuum. The crude product was purified with prep-HPLC [YMC Triart C18 150 × 25 mm × 5 um; A: water (FA); B: ACN; B%: 18% - 48% over 10min] to afford the title compound (92 mg, 22% yield) as white solid. LCMS (ESI, M+1): m / z = 467.1.  [000261] Step B. 4-(6-cyclopropyl-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol: A mixture of 7-bromo-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine (82 mg, 1.0 equiv), 5-ethyl-6- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (83.2 mg, 1.50 equiv), RuPhos-Pd-G3 (14.7 mg, 0.1 equiv), RuPhos (24.6 mg, 0.3 equiv) and Cs2CO3 (171 mg, 3.0 equiv) in dioxane (5 mL) and H2O (1.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The mixture was poured into water (1.0 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 2 mL). The organic phase was dried over Na2SO4and concentrated under vacuum. The crude product was purified with prep- HPLC [Phenomenex luna C18150 × 25 mm× 10 um; A; water(FA); B: ACN; B%: 22% - 52% over 10 min] afford the title compound (14.6 mg, 14% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.66-7.62 (m, 1H), 7.49 (s, 1H), 7.32-7.17 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H), 5.46-5.25 (m, 1H), 4.43-4.25 (m, 2H), 3.62-3.49 (m, 1H), 3.46 (s, 6H), 3.40-3.33 (m, 2H), 3.15- 3.06 (m, 1H), 2.65-2.53 (m, 1H), 2.48-2.17 (m, 4H), 2.11-2.01 (m, 2H), 1.99-1.86 (m, 1H), 1.51- 1.39 (m, 1H), 0.80-0.56 (m, 7H); LCMS (ESI, M+1): m / z = 577.5. [000262] EXAMPLE 304-(4-(dimethylamino)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [000263] Step A. 4-(4-(dimethylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine (1.80 g, 1.0 equiv) and 5-ethyl-6-fluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.37 g, 1.2 equiv) in methoxycyclopentane (18 mL) was added Ad2nBuP-Pd-G3 (393 mg, 0.15 equiv) andCs2CO3 (326 mg, 3.0 equiv). The mixture was stirred at 90 °C for 12 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product purified by column chromatography [SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1] to afford the title compound (475 mg, 21% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.58-8.46 (m, 1H), 8.26 (s, 1H), 7.77-7.60 (m, 1H), 7.32-7.16 (m, 2H), 6.93-6.80 (m, 1H), 6.37-6.17 (m, 1H), 5.78-5.60 (m, 1H), 5.53-5.27 (m, 1H), 5.19-5.05 (m, 1H), 4.86 (s, 9H), 4.53-4.34 (m, 2H), 3.73- 3.56 (m, 1H), 3.55 (s, 6H), 3.44 (br s, 2H), 3.24-3.16 (m, 1H), 2.59-2.34 (m, 3H), 2.31-2.20 (m, 2H), 2.19-2.09 (m, 2H), 2.05-1.95 (m, 1H), 0.81-0.67 (m, 3H); LCMS (ESI, M+1): m / z = 563.2. [000264] Step B. 4-(4-(dimethylamino)-6-ethyl-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a Pd / C (20.0 mg, 10% purity) in MeOH (4 mL) was added 4-(4-(dimethylamino)-8-fluoro-2-(((2R, 7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol (200 mg, 1.0 equiv) at N2. The mixture was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 12 hours under H2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified with prep-HPLC [Phenomenex Synergi C18150 × 25 mm × 10 µm; A: water (FA), B:ACN; B%: 19%-49% over 10min) to afford the title compound (31 mg, 15% yield) as light yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.58-8.48 (m, 1H), 7.97-7.88 (m, 1H), 7.72-7.62 (m, 1H), 7.33-7.17 (m, 2H), 6.94-6.86 (m, 1H), 5.51-5.31 (m, 1H), 4.55-4.36 (m, 2H), 3.71-3.54 (m, 2H), 3.52 (s, 6H), 3.50-3.44 (m, 1H), 3.26-3.17 (m, 1H), 2.62-2.45 (m, 2H), 2.45-2.25 (m, 4H), 2.22-2.10 (m, 3H), 2.06-1.94 (m, 1H), 1.11-0.98 (m, 3H), 0.79-0.70 (m, 3H); LCMS (ESI, M+1): m / z = 565.2. [000265] EXAMPLE 31  4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000266] Step A. 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-N,N,6-trimethylquinazolin-4-amine: A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-6-iodo-N,N-dimethylquinazolin-4-amine (500 mg, 1 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (516 µL, 2 equiv) and K3PO4 (1.5 M, 1.8 mL, 3 equiv), Pd(dppf)Cl2 (66 mg, 0.1 equiv) in dioxane (5 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 50 °C for 12 hours under N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (4 × 10 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with reversed phase flash [C18, 0.1 % formic acid condition] and prep-TLC (Dichloromethane / Methanol=5 / 1) to afford the title compound (50 mg, 12% yield) as white solid; LCMS (ESI, M+1): m / z = 441.1. [000267] Step B. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-N,N,6-trimethylquinazolin-4-amine (50 mg, 1 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (53.7 mg, 1.5 equiv) in dioxane (1 mL), Cs2CO3 (110 mg, 3 equiv) in H2O (0.2 mL), RuPhos (15.8 mg, 0.3 equiv) and RuPhos-Pd-G3 (9.5  mg, 0.1 equiv) was degassed and purged with N2 for 3 times and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The [000268] mixture was diluted with water (5 mL), extracted with ethyl acetate (4 × 5 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA), B: ACN; B%: 14%-44%, 2min] and lyophilized to afford the title compound (19.2 mg, 30% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.89 (s, 1H), 7.68-7.64 (m, 1H), 7.31- 7.14 (m, 2H), 6.87 (d, J = 2.4 Hz, 1H), 5.47-5.20 (m, 1H), 4.40-4.34 (m, 1H), 4.32-4.25 (m, 1H), 3.48-3.45 (s, 6H), 3.44-3.34 (m 3H), 3.14-3.04 (m, 1H), 2.66-2.53 (m, 1H), 2.48-2.25 (m, 2H), 2.24-2.15 (m, 2H), 2.11-1.99 (m, 5H), 1.99-1.88 (m, 1H), 0.77-0.73 (m, 3H); LCMS (ESI, M+1): m / z = 551.3. [000269] EXAMPLE 32(5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione [000270] Step A. 7-bromo-6-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(2,2,2-trifluoroethoxy)quinazoline: To a mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazoline (500 mg, 1.0 equiv) in dioxane (5 mL) was added 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (161 mg, 0.9 equiv), DIEA (656 mg, 4.0 equiv) and 4Å molecular sieve (50 mg). The mixture was stirred at 40 °C for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (30 mL). The mixture was extracted with EtOAc (20 mL ). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed phase flash [water (0.1%FA) / acetonitrile]. The desired fractions were collected and neutralized with solid NaHCO3, and concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the title compound (210 mg, 33% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 8.02 (d, J = 1.8 Hz, 1H), 5.35 - 5.23 (m, 2H), 4.14 (s, 2H), 3.00 - 2.90 (m, 2H), 2.58 (br s, 2H), 1.92 - 1.73 (m, 6H), 1.65 - 1.54 (m, 2H); LCMS (ESI, M+1, M+3): m / z = 498.0, 500.0. [000271] Step B. 6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: A mixture of 7-bromo-6-chloro-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline (240 mg, 1.0 equiv), 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (223 mg, 1.3 equiv), RuPhos Pd G3 (40.6 mg, 0.1 equiv), RuPhos (22.5 mg, 0.1 equiv) and Cs2CO3 (470 mg, 3.0 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (20 mL). Then the mixture was extracted with EA (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed phase flash [water (0.1%FA) / acetonitrile]. The desired fractions were collected and neutralized with solid NaHCO3 and concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the title compound (130 mg, 35% yield) as yellow solid; LCMS (ESI, M+1): m / z = 648.3.  [000272] Step C. (5R)-7-(6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione: To a solution of 6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline (130 mg, 1.0 equiv) in DMF (1 mL) and ACN (1 mL) was added (5R)- 1,3,9-triazaspiro[4.5]decane-2,4-dione (102 mg, 3.0 equiv) and K3PO4 (128 mg, 3.0 equiv). The reaction mixture was stirred at 40 °C for 16 hours. The mixture was filtered and the filtrate was purified by reversed phase flash [water (0.1%FA) / acetonitrile]. The desired fractions were collected and neutralized with solid NaHCO3 and concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (60 mg, 39% yield) as yellow solid; LCMS (ESI, M+1): m / z = 717.4. [000273] Step D. (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4- dione: To a solution of (5R)-7-(6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in DCM (1 mL) was added TFA (2 mL, 387 equiv). The reaction mixture was stirred at 0 °C for 1 hour. Then the mixture was stirred at 20 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 150 × 50mm × 3 µm; A: water (FA), B: ACN, B%: 10%-40% over 7min]. The desired fraction was collected and concentrated under vacuum to remove acetonitrile and lyophilized to afford the title compound (60 mg, 39% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.13 (s, 1H), 7.62 - 7.49 (m, 1H), 7.49 - 7.34 (m, 1H), 4.77 - 4.60 (m, 2H), 4.49 (br d, J = 13.2 Hz, 1H), 4.39 (br d, J = 13.2 Hz, 1H), 3.86 - 3.51 (m, 5H), 3.29 - 3.25 (m, 1H), 2.51 (s, 3H), 2.33 (br dd, J = 6.8, 11.8 Hz, 3H), 2.28 - 2.15 (m, 6H), 2.14 - 2.06 (m, 5H), 2.01 (br s, 1H); LCMS (ESI, M+1): m / z = 633.4. [000274] EXAMPLE 33  (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione[000275] Step A. 7-bromo-2,6-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (4.8 g, 1.0 equiv) in THF (40 mL) was added t-BuONa (2 M, 7.99 mL, 1.1 equiv) and 2,2,2-trifluoroethanol (1.45 g, 1.0 equiv) at -40 °C. The mixture was stirred at -40 °C for 1.5 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography afford the title compound (5.4 g, 94% yield) as yellow solid; LCMS (ESI, M+1): m / z = 394.8. [000276] Step B. 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo- 2,6-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (1 g, 1.0 equiv) in DMF (10 mL) were  added DIEA (984 mg, 1.33 mL, 3.0 equiv), 4Å molecular sieve (100 mg) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (485 mg, 1.2 equiv). The mixture was stirred at 60 °C for 12 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with reversed phase flash (C18, 0.1 % formic acid condition) afford the title compound (310 mg, 24% yield) as yellow solid; LCMS (ESI, M+1): m / z = 518.0. [000277] Step C. 6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline: To a solution of 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (250 mg, 1.0 equiv) in dioxane (2.5 mL) and H2O (0.5 mL) was added 5,6-dimethyl-1-tetrahydropyran- 2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (310 mg, 1.8 equiv), RuPhos Pd G3 (40.5 mg, 48.4 umol, 0.1 equiv), Cs2CO3 (473 mg, 3 equiv) and RuPhos (67.7 mg, 0.3 equiv). The mixture was stirred at 80 °C for 6 hours. The reaction mixture was filtered. The crude product was purified by column chromatography afford the title compound (239 mg, 74% yield) as white solid; LCMS (ESI, M+1): m / z = 666.3. [000278] Step D. (5R)-7-(6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 6-chloro-7- (5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (100 mg, 1.0 equiv) in DMF (0.8 mL) was added DIEA (58.21 mg, 3.0 equiv) and (5R)-1,3,9- triazaspiro[4.5]decane-2,4-dione (76.2 mg, 3.0 equiv). The mixture was stirred at 60 °C for 12 hours. The mixture was poured into water (3 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 4 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with reversed phase flash (C18, 0.1 % formic acid condition) afford the title compound (50 mg, 45% yield) as white solid; LCMS (ESI, M+1): m / z = 735.4. [000279] Step E. (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-  triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(6-chloro-7-(5,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30 mg, 1.0 equiv) in DCM (0.3 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition saturated NaHCO3 solution 4 mL at 0°C. The reaction mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated and purified with prep-HPLC [Waters Xbridge 150 × 25 mm × 5 um; mobile phase: A: water (ammonia hydroxide) B: ACN; B%: 24% - 54% over 9min] afford the title compound (8.78 mg, 27% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.08 (d, J = 1.3 Hz, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 5.38-5.22 (m, 1H), 4.38 (s, 2H), 4.24 (s, 2H), 3.64- 3.61 (m, 1H), 3.55-3.47 (m, 1H), 3.26-3.15 (m, 3H), 3.03-2.94 (m, 1H), 2.50 (s, 3H), 2.38-2.19 (m, 3H), 2.12 (s, 3H), 2.09-2.03 (m, 2H), 2.01-1.88 (m, 5H); LCMS (ESI, M+1): m / z = 651.2. [000280] EXAMPLE 344-(6-chloro-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000281] Step A. 4-(6-chloro-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,N- dimethylquinazolin-4-amine (200 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-  dioxaborolan-2-yl)naphthalen-2-ol (205 mg, 1.5 equiv), Cs2CO3 (423 mg, 3.0 equiv) and RuPhos (60.6 mg, 0.3 equiv) in dioxane (1.5 mL) and H2O (0.3 mL) was added RuPhos-Pd-G3 (36.2 mg, 0.1 equiv). The mixture was stirred at 90 °C for 3 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated. The residue was purified by reversed phase flash [C18, 0.1 % formic acid condition]. The crude product was purified with prep-HPLC [Phenomenex C1875 × 30 mm × 3 µm; A: water (FA), B: ACN; B%: 18%-48% over 7 min] and [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN; B%: 54%-84% over 7 min] and lyophilized to afford the title compound (21.6 mg, 8.7% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.13 (br s, 1H), 7.73-7.57 (m, 1H), 7.34-7.12 (m, 2H), 6.90 (br s, 1H), 5.43-5.15 (m, 1H), 4.37-4.14 (m, 2H), 3.53-3.39 (m, 6H), 3.28-3.11 (m, 3H), 3.08-2.93 (m, 1H), 2.67-2.51 (m, 1H), 2.40-2.17 (m, 3H), 2.16-2.08 (m, 1H), 2.02-1.82 (m, 3H), 0.80 (br s, 3H); LCMS (ESI, M+1): m / z = 571.4. [000282] EXAMPLE 35(5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione  [000283] Step A. 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline: A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (350 mg, 1.0 equiv), 5,6- dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (310 mg, 1.2 equiv), Cs2CO3 (1 M, 2.18 mL, 3.0 equiv) in methoxycyclopentane (10 mL) was degassed and purged with N2 for 3 times, Ad2nBuP-Pd-G3 (52.9 mg, 0.1 equiv) was added and the mixture was stirred at 80 °C for 6 hours under N2 atmosphere. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 8 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase flash (0.1% FA condition) to afford the title compound (350 mg, 71% yield) as white solid; LCMS (ESI, M+1): m / z = 632.3. [000284] Step B. (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (2,2,2-trifluoroethoxy)quinazoline (100 mg, 1.0 equiv), (R)-1,3,7-triazaspiro[4.5]decane-2,4- dione (40.2 mg, 1.5 equiv) and DIEA (61.4 mg, 82.7 µL, 3.0 equiv) in DMF (0.5 mL) was added 4 Å MS (25.0 mg). The mixture was stirred at 40 °C for 144 hours. The reaction mixture was filtered, washed with DMF (2 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-  HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water( NH4HCO3)- ACN];B%: 43%-73%, 10 min] and lyophilized to afford the title compound to afford the title compound (50.0 mg, 45% yield) as white solid; LCMS (ESI, M+1): m / z = 701.4. [000285] Step C. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane- 2,4-dione: To a solution of (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)- 1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in dichloromethane (0.5 mL) was added TsOH (122 mg, 10 equiv).The mixture was stirred at 0 °C for 0.5 hour. The mixture was quenched with water (1 mL) and extracted with ethyl acetate (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 9 min] and lyophilized to afford the title compound (5.38 mg, 9.0% yield) as white solid; SFC: Chiralpak IG-350×4.6mm I.D., 3μm [40% EtOH (0.05% DEA)] in CO2, flow rate: 3 mL / min, detector: 220 nm, tR1 = 0.737 min，tR2 = 1.437 min;1H NMR (400 MHz, METHANOL- d4) δ = 7.95 (d, J = 8.4 Hz, 1H), 7.55-7.43 (m, 2H), 7.31 (dd, J = 6.8, 8.4 Hz, 1H), 5.41 (br s, 1H), 5.28 (br s, 1H), 4.60-4.37 (m, 2H), 4.31 (s, 2H), 3.73-3.64 (m, 1H), 3.62-3.51 (m, 1H), 3.49-3.38 (m, 1H), 3.14-2.99 (m, 1H), 2.50 (s, 3H), 2.45-2.25 (m, 2H), 2.25-2.14 (m, 6H), 2.10-1.86 (m, 7H); LCMS (ESI, M+1): m / z = 617.3. [000286] EXAMPLE 367-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one  [000287] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: A mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50.0 mg, 1.0 equiv), 1,3,9- triazaspiro[4.5]decan-2-one (50.0 mg, 3.6 equiv), K3PO4 (37.8 mg, 2.0 equiv) and 4Å molecular sieve (25 mg) in DMF (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 hours under N2 atmosphere. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (column: Phenomenex Synergi C18150 × 25mm × 10um;mobile phase: [water(FA) - ACN]; B%: 18% - 38%, 10min) lyophilized to afford the title compound (29.0 mg, 53% yield, 0.51 FA ) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.93-7.84 (m, 1H), 7.70-7.60 (m, 1H), 7.37-7.29 (m, 1H), 7.27-7.19 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 4.43-4.34 (m, 2H), 4.00-3.74 (m, 4H), 3.46- 3.35 (m, 1H), 3.30-3.27 (m, 1H), 2.82 (br s, 2H), 2.72-2.52 (m, 6H), 2.49-2.35 (m, 2H), 2.05-1.82 (m, 4H), 0.84 (s, 2H), 0.77 (q, J = 7.2 Hz, 3H), 0.66 (s, 2H); LCMS (ESI, M+1): m / z = 617.3 [000288] EXAMPLE 37  7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2- dioxide[000289] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (10.0 mg, 1.0 equiv), 2λ6-thia-1,3,9-triazaspiro[4.5]decane 2,2-dioxide (10.2 mg, 3.0 equiv) and 4Å molecular sieve (10.0 mg,1.0 equiv) in DMF (0.5 mL) was added K3PO4 (11.34 mg, 3.0 equiv)). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (77.8 mg, 67% yield, 0.95 FA) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.96 (br d, J = 8.4 Hz, 1H), 7.73- 7.60 (m, 1H), 7.38-7.32 (m, 1H), 7.27-7.20 (m, 2H), 6.96-6.93 (m, 1H), 4.53-4.33 (m, 3H), 4.23 (br t, J = 14.4 Hz, 1H), 3.81-3.58 (m, 2H), 3.42 (d, J = 11.6 Hz, 1H), 3.27-3.12 (m, 3H), 2.89 (s, 6H), 2.56-2.37 (m, 2H), 2.14-1.98 (m, 2H), 1.97-1.81 (m, 2H), 0.95 (s, 2H), 0.85 - 0.72 (m, 5H); LCMS (ESI, M+1): m / z = 653.3 [000290] EXAMPLE 38  6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one[000291] Step A. 8-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-quinazolin-4-yl]-1,8-diazaspiro[3.5]nonan-2-one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50.0 mg, 1 equiv) and 1,6- diazaspiro[3.5]nonan-2-one (37.4 mg, 3.0 equiv) in DMF (0.1 mL) and MeCN (0.1 mL) was added K3PO4 (56.7 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hours. The mixture was quenched with water (3 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (3 × 2 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water( NH4HCO3)-ACN];B%: 36%-66%,9 min ] and lyophilized to afford the title compound (25.3 mg, 46% yield) as yellow solid. SFC: Chiralcel OD-350 × 4.6 mm I.D., 3 μm [MeOH (0.05% DEA) in CO2 from 5% to 40%)] in CO2, flow rate: 3mL / min, detector: 220 nm, tR1: 2.029 min, tR2: 2.124 min, tR3: 2.254 min;1H NMR (400 MHz, METHANOL-d4) δ = 7.84 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 6.4, 9.2 Hz, 1H), 7.36-7.16 (m, 3H), 6.95 (d, J = 2.8 Hz, 1H), 4.36 (t, J = 3.6 Hz, 2H), 4.22- 4.02 (m, 2H), 3.96-3.82 (m, 1H), 3.76-3.56 (m, 1H), 2.92-2.72 (m, 2H), 2.56-2.36 (m, 4H), 2.32  (s, 6H), 2.12-1.92 (m, 4H), 0.86-0.66 (m, 5H), 0.56-0.46 (m, 2H) ; LCMS (ESI, M+1): m / z = 602.3. [000292] EXAMPLE 395-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)- dione[000293] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8- fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50.0 mg, 1.0 equiv) in DMF (0.5 mL) was added 2,3,3a,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-4,6-dione (25.0 mg, 2.0 equiv), ACN (0.5 mL) and K3PO4 (56.7 mg, 3.0 equiv). The mixture was stirred at 60 °C for 24 hours. The reaction mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN]; B%: 12%-42%, 10min) to afford the title compound (36.5 mg, 30.8% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.07 (br d, J = 8.8 Hz, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.36 (br t, J = 8.0 Hz, 1H), 7.28 - 7.20 (m,  2H), 6.96 (s, 1H), 4.76 - 4.61 (m, 2H), 4.38 (s, 2H), 4.25 - 4.12 (m, 2H), 3.68 (br d, J = 7.2 Hz, 2H), 2.99 (s, 2H), 2.84 - 2.68 (m, 6H), 2.49 - 2.36 (m, 2H), 0.89 (s, 2H), 0.82 - 0.71 (m, 5H); LCMS (ESI, M+1): m / z = 602.4. [000294] EXAMPLE 407-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione[000295] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4- dione: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv), 1,3,9- triazaspiro[4.5]decane-2,4-dione (60.3 mg, 2.0 equiv) and 4Å molecular sieve (10 mg) in DMF (0.5 mL) was added DIEA (69.0 mg, 3.0 equiv). The mixture was stirred at 60 °C for 24 hours. The residue was filtered and washed with DMF (1 mL) and purified with prep-HPLC [Phenomenex C1875 × 30 mm × 3 µm; A: water (FA), B: ACN; B%: 15%-45% over 7 min] and lyophilized to afford the title compound (54.6 mg, 47% yield) as yellow solid;1H NMR (400 MHz,  METHANOL-d4) δ = 7.88 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 6.0, 9.2 Hz, 1H), 7.37-7.29 (m, 1H), 7.28-7.17 (m, 2H), 6.96 (d, J = 2.4 Hz, 1H), 4.51-4.22 (m, 4H), 3.71 (dd, J = 13.6, 15.2 Hz, 1H), 3.65-3.47 (m, 1H), 3.10-2.90 (m, 2H), 2.85-2.63 (m, 6H), 2.53-2.33 (m, 2H), 2.28-2.13 (m, 1H), 2.11-1.86 (m, 3H), 0.89 (s, 2H), 0.81-0.67 (m, 5H); LCMS (ESI, M+1): m / z = 631.3. [000296] EXAMPLE 415-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000297] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 4-(2-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv), N,N-dimethyl-5,6,7,8-tetrahydro-4H-  pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (167 mg, 3.0 equiv) and 4Å molecular sieve (50 mg) in DMF (0.05 mL) was added DIEA (103 mg, 3.0 equiv). The mixture was stirred at 100 °C for 24 hours. The residue was filtered and washed with DMF (1 mL) and purified with prep-HPLC [Phenomenex C1875 × 30 mm × 3 µm; A: water (FA), B: ACN; B%: 18% - 48% over 7 min] to give a crude product. The crude product was purified with prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN; B%: 35% - 65% over 9 min] and lyophilized to afford the title compound (23.2 mg, 13% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.91 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (dd, J = 6.8, 8.8 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 6.67 (s, 1H), 5.27-5.03 (m, 2H), 4.60-4.48 (m, 2H), 4.40- 4.24 (m, 4H), 3.34 (s, 3H), 3.08 (s, 3H), 2.52-2.43 (m, 3H), 2.42-2.35 (m, 3H), 2.31 (s, 6H), 0.76 (t, J = 7.2 Hz, 3H), 0.73-0.66 (m, 2H), 0.58-0.46 (m, 2H); LCMS (ESI, M+1): m / z = 670.4. [000298] EXAMPLE 424-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol[000299] Step A. 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6- ol: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.0 equiv) and 6-methyl- 1,4-oxazepan-6-ol (199 mg, 0.9 equiv) in dichloromethane (5 mL) was added DIEA (655 mg, 3 equiv) .The mixture was stirred at 0-20 °C for 16 hour. The reaction mixture was quenched by  addition of water (10 mL) and was extracted with ethyl acetate (3 ×10 mL). The combined organic layers were washed with saturated brine (3 ×10 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reversed-phase flash (0.1% FA condition) to afford the title compound (150 mg, 41% yield) as yellow solid; Column: Chiralcel OD-350×4.6mm I.D., 3 μm [MeOH (0.05% DEA) in CO2 from 5% to 40%)] in CO2, flow rate: 3 mL / min, detector: 220 nm, tR1: 2.029 min, tR2: 2.124 min, tR3: 2.254 min;1H NMR (400 MHz, DMSO-d6) δ = 8.24-8.14 (m, 1H), 7.78-7.63 (m, 1H), 5.09 (s, 1H), 4.25-4.10 (m, 2H), 4.07-3.88 (m, 3H), 3.78 (ddd, J = 3.2, 6.8, 14.4 Hz, 1H), 3.57-3.48 (m, 2H), 1.11 (s, 3H); LCMS (ESI, M+1): m / z = 391.9. [000300] Step B. 4-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8- fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To solution of 4-(7-bromo-2-chloro-8- fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (270 mg, 1.0 equiv) in DMSO (3 mL) was added (1-((dimethylamino)methyl)cyclopropyl)methanol (179 mg, 2.0 equiv) , DIEA (268 mg, 3 equiv) and 4Å molecular sieve (80.0 mg), and the reaction mixture was stirred at 80 °C for 36 hours. The reaction mixture was quenched by addition of water (10 mL) and was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (3 × 10 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reversed-phase flash (0.1% FA condition) to afford the title compound (8.33 mg, 20% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.13 (s, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 5.42-5.22 (m, 1H), 4.41-4.24 (m, 2H), 4.02-3.90 (m, 2H), 3.27-3.13 (m, 3H), 3.05- 2.98 (m, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.50 (br s, 1H), 2.39-2.19 (m, 2H), 2.18-2.10 (m, 2H), 2.04- 1.90 (m, 3H), 0.78 (t, J = 7.2 Hz, 3H). [000301] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: A mixture of 4-[7-bromo-2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-8-fluoro- quinazolin-4-yl]-6-methyl-1,4-oxazepan-6-ol (130 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (128 mg, 1.5 equiv), Ad2nBuP-Pd-G3 (39.2 mg, 0.2 equiv), Cs2CO3 (1 M, 807 μL, 3.0 equiv) in CPME (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hour under N2 atmosphere. The  reaction mixture was quenched by addition of water (10 mL) and was extracted with ethyl acetate (3 ×10 mL). The combined organic layer was washed with saturated brine (3 ×10 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm;mobile phase: [water(FA)-ACN];B%: 16%-46%, 10 min) to afford the title compound (150 mg, 41% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.60-8.49 (m, 1H), 8.25-8.13 (m, 1H), 7.72-7.61 (m, 1H), 7.39-7.30 (m, 1H), 7.28-7.19 (m, 2H), 7.00-6.93 (m, 1H), 4.53-4.31 (m, 4H), 4.18-3.88 (m, 4H), 3.75-3.60 (m, 2H), 3.18-2.97 (m, 2H), 2.82 (s, 6H), 2.56-2.37 (m, 2H), 1.30- 1.21 (m, 3H), 0.95-0.88 (m, 2H), 0.83-0.73 (m, 5H); LCMS (ESI, M+1): m / z = 593.4. [000302] EXAMPLE 434-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000303] Step A. 7-bromo-2-chloro-8-fluoro-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (600 mg, 1.0 equiv) and DIEA (786 mg, 3.0 equiv) in DCM (5 mL) was added N-methylmethanamine (2M in THF, 979 mg, 10 equiv) dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with DCM (4 ×10 mL). The organic phase was dried over Na2SO4, concentrated and purified with reversed phase flash [C18, 0.1% FA] to afford the title compound (320 mg, 47% yield) as yellow solid; LCMS (ESI, M+1): m / z = 305.9.  [000304] Step B. 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2-chloro-8-fluoro-N,N- dimethyl-quinazolin-4-amine (250 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (196 mg , 1.5 equiv) in dioxane (2 mL) was added DIEA (265 mg, 2.5 equiv) and 4Å molecular sieve (25 mg). The mixture was stirred at 100 °C for 120 hours. The reaction mixture was filtered and purified with reversed phase flash [C18, 0.1% FA] to afford the title compound (180 mg, 49% yield) as yellow solid; LCMS (ESI, M+1): m / z = 427.1. [000305] Step C. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 7- bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-N,N- dimethylquinazolin-4-amine (150 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-ol (166 mg, 1.5 equiv) and K3PO4 (1.5 M in H2O, 3.0 equiv) in methoxycyclopentane (1.5 mL) was added Ad2nBuP-Pd-G3 (50 mg, 0.1 equiv) under N2 atmosphere. The mixture was stirred at 90 °C for 1 hour under N2 atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified with reversed phase flash [C18, 0.1% FA] and prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: water(FA)-CAN; B%: 15%-45%, 10 minutes] to afford the title compound (91.21 mg, 45.51% yield, 0.61FA) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.06 (br d, J = 8.6 Hz, 1H), 7.64 (br dd, J = 6.0, 8.8 Hz, 1H), 7.29-7.22 (m, 1H), 7.41-7.10 (m, 2H), 6.95 (s, 1H), 5.58- 5.34 (m, 1H), 4.66-4.37 (m, 2H), 3.84-3.60 (m, 3H), 3.50 (s, 6H), 3.31-3.12 (m, 1H), 2.63-2.02 (m, 8H), 0.77 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 537.2. [000306] EXAMPLE 44 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol[000307] Step A. 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7- yl)naphthalen-2-ol (100 mg, 1.0 equiv) and 5,6,7,8-tetrahydro-4H-triazolo[1,5-a][1,4]diazepine (59.0 mg, 2.0 equiv, HCl) in DMF (0.1 mL) and ACN (0.1 mL) was added K3PO4 (215 mg, 6.0 equiv). The mixture was stirred at 40 °C for 72 hours. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with prep-HPLC [Phenomenex Gemini-NX C18150 × 25mm × 10µm; A: (water(FA)), B: ACN]; B%: 15%-45% over 10min) to afford the title compound (10 mg, 9.1% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 8.02-7.90 (m, 1H), 7.72-7.58 (m, 1H), 7.44-7.29 (m, 1H), 7.29- 7.19 (m, 2H), 7.19-7.18 (m, 1H), 6.93 (dd, J = 2.4, 7.2 Hz, 1H), 5.54-5.14 (m, 2H), 4.83-4.72 (m, 1H), 4.49-4.29 (m, 3H), 3.66-3.32 (m, 5H), 3.27-3.09 (m, 1H), 2.71-1.83 (m, 10H), 0.77 (q, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 630.2. [000308] EXAMPLE 45  7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide[000309] Step A. 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline: A mixture of 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (350 mg, 1.0 equiv), (5- chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane (433 mg, 1.2 eq), CuI (40.0 mg, 0.3 equiv) and BINAP (87.1 mg, 0.2 equiv) in toluene (3 mL) was degassed and purged with N2 for 3 times. Pd(dppf)Cl2 (51.2 mg, 0.1 equiv) was added and the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The mixture was filtered. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4, concentrated and purified with reversed phase flash [C18, 0.1% FA] to afford the tittle compound (130 mg, 16% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 772.1, 774.1. [000310] Step B. 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(8-chloro-7-fluoro-3-  ((triisopropylsilyl)oxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (70.0 mg, 1.0 equiv) and 2-thia- 1,3,7-triazaspiro[4.5]decane 2,2-dioxide (32.6 mg, 1.5 equiv) in DMF (0.8 mL) was added K3PO4 (72.4 mg, 3.0 equiv) and 4Å molecular sieve (20 mg). The mixture was stirred at 60 °C for 12 hours. The mixture was filtered and purified with prep-HPLC [Phenomenex Synergi C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 20%-40%, 10 minutes] to afford the title compound (19.6 mg, 23% yield, 0.42FA) as yellow solid;1H NMR (400 MHz, methanol-d4) δ = 7.87-7.75 (m, 1H), 7.66 (br dd, J = 2.8, 9.6 Hz, 1H), 7.44-7.32 (m, 2H), 7.15-7.11 (m, 1H), 5.55- 5.31 (m, 1H), 4.57-4.41 (m, 2H), 4.40-4.27 (m, 1H), 4.27-4.10 (m, 1H), 3.77-3.46 (m, 6H), 3.42 (br d, J = 11.2 Hz, 1H), 3.22 (br d, J = 11.2 Hz, 2H), 2.65-2.24 (m, 4H), 2.16 (br s, 2H), 2.05 (br d, J = 9.2 Hz, 3H), 1.95-1.78 (m, 2H); LCMS (ESI, M+1): m / z = 707.0 [000311] EXAMPLE 46(5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione  [000312] Step A. 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline: To a mixture of 7-bromo-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (350 mg, 1 equiv), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (374 mg, 1.5 equiv) in methoxycyclopentane (3.5 mL) was added Cs2CO3(1.5 M, 1.40 mL, 3 equiv) at 25 °C. The mixture was degassed and purged with N2for 3 times, and then Ad2nBuP-Pd-G3 (51.0 mg, 70.0 umol, 0.1 equiv) was added. The reaction was degassed and purged with N2 for 3 times and stirred at 90 °C for 2 hours under N2 atmosphere. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified with reversed-phase HPLC [ 0.1% FA condition] to afford the title compound (357 mg, 78% yield) as a white solid; LCMS (ESI, M+1): m / z= 650.4. [000313] Step B. (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)- 1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-  yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (280 mg, 1 equiv), (R)-1,3,7- triazaspiro[4.5]decane-2,4-dione (146 mg, 2 equiv) in DMF (1.4 mL) and ACN (1.4 mL) was added K3PO4 (274 mg, 3 equiv) and 4Å molecular sieve (250 mg). The mixture was degassed and purged with N2 for 3 times, and stirred at 60 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with reversed-phase HPLC [0.1% NH3•H2O] to afford the title compound (140 mg, 45% yield) as a yellow solid;1H NMR (400 MHz, methanol-d4) δ = 7.71 (d, J = 9.6 Hz, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 5.82 (br d, J = 8.4 Hz, 1H), 5.43 - 5.18 (m, 1H), 4.41 - 4.29 (m, 2H), 4.25 (s, 2H), 4.03 (br d, J = 11.6 Hz, 1H), 3.84 (dt, J = 2.4, 11.2 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.52 - 3.41 (m, 1H), 3.28 - 3.16 (m, 2H), 3.07 - 2.95 (m, 1H), 2.53 (s, 3H), 2.52 - 2.44 (m, 1H), 2.41 - 2.09 (m, 8H), 2.08 - 1.83 (m, 9H), 1.81 - 1.59 (m, 2H); LCMS (ESI, M+1): m / z= 719.5. [000314] Step C. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione: To a solution of (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1 equiv) in MeOH (0.4 mL) was added HCl•MeOH (4 M, 28.7 equiv) and stirred at 20 °C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified with prep-HPLC [column: Waters Xbridge 150 × 25mm × 5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 20%-50%, 9 minutes] to afford the title compound (14.3 mg, 39% yield) as a white solid;1H NMR (400 MHz, methanol-d4) δ = 7.72 (br d, J = 10.0 Hz, 1H), 7.51 (d, J = 10.0 Hz, 2H), 5.44 - 5.15 (m, 1H), 4.42 - 4.29 (m, 2H), 4.29 - 4.19 (m, 2H), 3.58 (dd, J = 4.4, 13.2 Hz, 1H), 3.47 - 3.37 (m, 1H), 3.24 - 3.14 (m, 2H), 3.07 - 2.94 (m, 1H), 2.50 (s, 3H), 2.41 - 2.07 (m, 8H), 2.07 - 1.74 (m, 6H); LCMS (ESI, M+1): m / z= 635.5. [000315] EXAMPLE 47  5-(6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000316] Step A. 6,8-difluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazoline-2,4- diol: A mixture of 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (425 mg, 1.5 equiv), 7-bromo-6,8-difluoro-quinazoline-2,4-diol (250 mg, 1.0 equiv), Cs2CO3 (882 mg, 3.0 equiv) and Ad2nBuP-Pd-G3 (65.7 mg, 0.1 equiv ) in ethyl alcohol (20 mL) and water (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 1.5 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE / EA= 3 / 1) to afford the title compound (120 mg, 14.1% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.89-7.75  (m, 2H), 7.62-7.36 (m, 5H), 5.42-5.27 (m, 2H), 3.61-3.52 (m, 3H); LCMS (ESI, M+1): m / z = 385.0 [000317] Step B.4-(2,4-dichloro-6,8-difluoroquinazolin-7-yl)naphthalen-2-ol: A mixture of 6,8-difluoro-7-[3-(methoxymethoxy)-1-naphthyl]quinazoline-2,4-diol (30.0 mg, 1.0 equiv ), POCl3 (144 mg, 12 equiv) and DIEA (40.3 mg, 4.0 equiv) were stirred at 130 °C for 0.2 hour under N2 atmosphere. The mixture was concentrated under reduced pressure to afford the title compound (30 mg, crude) as yellow oil which was used into the next step without further purification. [000318] Step C 5-(2-chloro-6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)- N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of 4-(2,4-dichloro-6,8-difluoroquinazolin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv), N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (37.1 mg, 1.5 equiv) and DIEA (46.0 mg, 3.0 equiv) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at -40 °C for 1 hour under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN];B%: 39%- 69%,10min ) to afford the title compound (10 mg, 15% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 549.4 [000319] Step D. 5-(6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-N,N- dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of 5-[2- chloro-6,8-difluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (10 mg, 1 equiv) and Pd / C (5 mg, 10% purity, 0.1 equiv) in MeOH (2 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 1 hour under H2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 × 50mm × 3 um; mobile phase: [water(FA)-ACN]; B%: 28%-58%,7min) to afford the title compound (1.08 mg, 11% yield) as an off-white solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.64 (s, 1H), 7.83-7.75 (m, 2H), 7.47-7.40 (m, 1H), 7.35 (br d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.27-7.20 (m, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H), 5.18 (s, 2H), 4.59 (s, 4H), 3.35 (s, 2H), 3.34 (s, 3H), 3.08 (s, 3H); LCMS (ESI, M+1): m / z = 515.3  [000320] EXAMPLE 48(3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000321] Step A. (R)-1-(7-bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-bromo-2-chloro- 6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv) in DMSO (0.3 mL) was added (hexahydro-1H-pyrrolizin-7a-yl)methanol (719 mg, 10 equiv). The mixture was stirred at 90 °C for 12 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 8 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase flash (0.1% FA condition) to afford the title compound (130 mg, 42% yield) as white solid. LCMS (ESI, M+1, M+3): m / z = 497.1, 499.1 [000322] Step B. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: A mixture of (R)-1-(7-bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol (100 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-ol (95.4 mg, 1.5 eq), Ad2nBuP-Pd-G3 (14.6 mg, 0.1 equiv),  K3PO4 (2 M, 301 μL, 3.0 equiv) in CPME (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N2 atmosphere. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 8 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed-phase flash (0.1% FA condition) to afford the title compound (130 mg, 42% yield) as white solid. SFC: Chiralpak IG-350×4.6mm I.D., 3μm [40% EtOH (0.05% DEA)] in CO2, flow rate: 3 mL / min, detector: 220 nm, tR1 = 1.106 min，tR2 = 1.615 min;1H NMR (400 MHz, METHANOL-d4) δ = 7.82 (br d, J = 10.4 Hz, 1H), 7.68 (dd, J = 5.6, 8.4 Hz, 1H), 7.34-7.18 (m, 2H), 6.98 (d, J = 2.8 Hz, 1H), 4.47 (br s, 2H), 4.31 (br s, 1H), 4.11 (br d, J = 13.2 Hz, 1H), 3.603.46 (m, 1H), 3.44-3.36 (m, 3H), 3.10-2.90 (m, 2H), 2.66-2.36 (m, 2H), 2.32-2.16 (m, 3H), 2.02 (br s, 4H), 1.96-1.92 (m, 2H), 1.86-1.82 (m, 1H), 1.82-1.72 (m, 2H), 1.36-1.22 (m, 3H), 0.81 (q, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 607.2. [000323] EXAMPLE 497-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one  [000324] Step A. 1-(1-(((7-bromo-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2- yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a solution of 7-bromo-2-chloro-6,8- difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (3.0 g, 1.0 equiv) and (1- ((dimethylamino)methyl)cyclopropyl)methanol (1.03 g, 1.0 equiv) in DMF (15 mL) was added DIPEA (2.05 g, 2.0 equiv) and 4Å molecular sieve (200 mg). The mixture was stirred at 40 °C for 14 hours under N2 atmosphere. The reaction mixture was filtered. The filtrate was purified with reversed phase flash [water (FA, 0.1%) / acetonitrile = 3 / 1] to afford the title compound (0.93 g, 22% yield) as light yellow solid; LCMS (ESI, M+1, M+3): m / z = 470.1, 472.1. [000325] Step B. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 1-(1- (((7-bromo-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N- dimethylmethanamine (1 g, 1 equiv) and 5-ethyl-6-fluoro-4-(4,4,5-trimethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-2-ol (1 g, 1.5 equiv) in methoxycyclopentane (20 mL) was added Cs2CO3 (1.5 M in H2O, 4.25 mL, 3.0 equiv) and Ad2nBuP-Pd-G3 (155 mg, 0.1 equiv) under N2 atmosphere. The mixture was stirred at 70 °C for 12 hours. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (4 × 20 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified with reversed phase flash [water (FA, 0.1%) / acetonitrile=3 / 2] to afford the tittle compound (0.87 g, 68% yield) was obtained as light yellow solid; LCMS (ESI, M+1): m / z = 580.2. [000326] Step C. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-  one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (170 mg, 1 equiv) and 1,3,7-triazaspiro[4.5]decan-2-one (91 mg, 2.0 equiv) in DMF (1 mL) was added 4Å molecular sieve (20 mg) and K3PO4 (124 mg, 2.0 equiv). The mixture was stirred at 60 °C for 13 hours under N2 atmosphere. The mixture was filtered. The filtrate was purified with prep-HPLC [column: Phenomenex Synergi C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 17%-47%, 10 minutes] to afford the tittle compound (17.3 mg, 9% yield, 0.27FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.70-7.65 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 4.40-4.37 (m, 2H), 3.87-3.82 (m, 4H), 3.42 (d, J = 9.2 Hz, 1H), 3.30-3.28 (m, 1H), 2.70-2.66 (m, 2H), 2.59-2.41 (m, 8H), 2.03-1.93 (m, 4H), 0.84-0.78 (m, 5H), 0.62-0.59 (m, 2H); LCMS (ESI, M+1): m / z = 635.3. [000327] EXAMPLE 507-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2- dioxide [000328] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide: To a solution of 4-(2-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equiv) and 2-thia- 1,3,7-triazaspiro[4.5]decane 2,2-dioxide (80 mg, 1.9 equiv) in DMF (0.9 mL) was added 4Å molecular sieve (20 mg) and K3PO4 (95 mg, 2.0 equiv). The mixture was stirred at 60 °C for 16 hours under N2 atmosphere. The mixture was filtered. The filtrate was purified with prep-HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 20%-50%, 10 minutes] to afford the tittle compound (82.4 mg, 49% yield, 0.83FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.73-7.67 (m, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.28-7.22 (m, 1H), 6.99 (dd, J = 2.8, 6.8 Hz, 1H), 4.47-4.31 (m, 3H), 4.25-4.15 (br s, 1H), 3.69 (br t, J = 13.2 Hz, 1H), 3.63-3.53 (m, 1H), 3.40 (dd, J = 3.2, 11.8 Hz, 1H), 3.21 (d, J = 12.0 Hz, 1H), 3.15 (br d, J = 3.2 Hz, 2H), 2.87 (s, 6H), 2.65-2.51 (m, 1H), 2.43 (ddd, J = 3.6, 7.2, 10.4 Hz, 1H), 2.04 (br d, J = 11.2 Hz, 2H), 1.93-1.87 (m, 2H), 0.95-0.91 (m, 2H), 0.81-0.79 (m, 5H); LCMS (ESI, M+1): m / z = 671.3. [000329] EXAMPLE 516-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one  [000330] Step A. 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (120 mg, 1 equiv) and 1,6- diazaspiro[3.5]nonan-2-one (60 mg, 2.1 equiv) in DMF (0.9 mL) was added 4Å molecular sieve (20 mg) and K3PO4 (88 mg, 2.0 equiv). The mixture was stirred at 60 °C for 11 hours under N2 atmosphere. The mixture was filtered. The filtrate was purified with prep-HPLC [column: Phenomenex Synergi C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 17%-47%, 10 minutes] to afford the tittle compound (70.0 mg, 50% yield, 0.67FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.70-7.65 (m, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 4.41-4.39 (m, 2H), 4.14-4.11 (m, 2H), 3.87-3.84 (m, 1H), 3.66 (ddd, J = 4.0, 8.4, 12.4 Hz, 1H), 3.34-2.98 (m, 2H), 2.89-2.83 (m, 1H), 2.77 (s, 6H), 2.75-2.73 (m, 1H), 2.62-2.49 (m, 1H), 2.42 (ddd, J = 2.8, 7.2, 14.4 Hz, 1H), 2.05-1.95 (m, 4H), 0.91-0.88 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H), 0.77 - 0.72 (m, 2H); LCMS (ESI, M+1): m / z = 620.3. [000331] EXAMPLE 52 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione[000332] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8- difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equiv) and tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (65 mg, 2.1 equiv) in DMF (0.9 mL) was added 4Å molecular sieve (20 mg) and K3PO4 (95 mg, 2.0 equiv). The mixture was stirred at 60 °C for 13 hours under N2 atmosphere. The mixture was filtered. The filtrate was purified with prep-HPLC [column: Phenomenex Synergi C18150 × 25 mm × 10 μm; mobile phase: water(FA)- ACN; B%: 18%-48%, 10 minutes] to afford the tittle compound (51.5 mg, 35% yield, 0.73FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.87 (br d, J = 10.0 Hz, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 4.65 (br dd, J = 5.2, 13.2 Hz, 2H), 4.41-4.38 (m, 2H), 4.18 (br dd, J = 8.8, 12.0 Hz, 2H), 3.69 (br d, J = 7.6 Hz, 2H), 3.10-3.02 (m, 2H), 2.81-2.78 (m, 6H), 2.55-2.49 (m, 1H), 2.47-2.42 (m, 1H), 0.91-0.88 (m, 2H), 0.81-0.76 (m, 5H); LCMS (ESI, M+1): m / z = 620.3. [000333] EXAMPLE 53  6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol[000334] Step E. 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equiv) and 6- azaspiro[3.5]nonan-2-ol (80 mg, 2.5 equiv) in DMF (0.9 mL) was added 4Å molecular sieve (20 mg) and K3PO4 (95 mg, 2.0 equiv). The mixture was stirred at 60 °C for 16 hours under N2 atmosphere. The mixture was filtered. The filtrate was purified with prep-HPLC [column: Phenomenex Synergi C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 18%-48%, 10 minutes] to afford the tittle compound (54.6 mg, 36% yield, 0.5FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.65-7.62 (m, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 4.39 (d, J = 3.2 Hz, 2H), 4.30-4.26 (m, 1H), 3.91-3.83 (m, 2H), 3.80-3.77 (m, 2H), 2.93 (br d, J = 4.8 Hz, 2H), 2.68 (br d, J = 3.6 Hz, 6H), 2.56 (br s, 1H), 2.44 (dt, J = 2.8, 7.2 Hz, 1H), 2.35-2.18 (m, 2H), 1.82-1.70 (m, 6H), 0.86-0.78 (m, 5H), 0.74-0.71 (m, 2H); LCMS (ESI, M+1): m / z = 621.3.  [000335] EXAMPLE 547-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione[000336] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4- dione: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4- (2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (60.0 mg, 1.0 equiv), 1,3,7-triazaspiro[4.5]decane-2,4-dione (35.0 mg, 2.0 equiv) and 4Å molecular sieve (10.0 mg, 1.0 equiv) in MeCN (0.2 mL) and DMF (0.2 mL) was added K3PO4 (65.9 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hrs. The reaction mixture was filtered and purified by prep-HPLC [column: Phenomenex Synergi C18150 × 25mm × 10um;mobile phase: [water(FA)-ACN]; B%: 18%-40%,11min] and lyophilized to afford the title compound (19.8 mg, 29% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.73 - 7.66 (m, 2H), 7.32 - 7.30 (m, 1H), 7.26 (t, J = 9.2 Hz, 1H), 7.01 - 6.96 (m, 1H), 4.45 - 4.36 (m, 3H), 4.35 - 4.34 (m, 1H), 4.35 (br s, 1H), 3.73 - 3.64 (m, 1H), 3.64 - 3.55 (m, 1H), 3.19 - 3.10 (m, 2H), 2.85 (s, 6H), 2.62 - 2.51 (m, 1H), 2.49 -  2.36 (m, 1H), 2.27 - 2.17 (m, 1H), 2.10 - 2.01 (m, 2H), 1.96 (br d, J = 13.6 Hz, 1H), 0.93 (m, 2H), 0.83 - 0.76 (m, 5H); LCMS (ESI, M+1): m / z = 649.4. [000337] EXAMPLE 555-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000338] Step A. 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 7-bromo-2,4- dichloro-6,8-difluoroquinazoline (1.00 g, 1.0 equiv), N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (597 mg, 0.9 equiv) and 4Å molecular sieve (100 mg, 1.0 equiv) in DCM (10 mL) was added DIEA (1.24 g, 3 equiv) at 0 °C, and then the mixture was stirred at 20 °C for 2 hrs. The reaction mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (1.50 g, 89% yield) as white solid; LCMS (ESI, M+1, M+3): m / z = 485.0, 487.0.  [000339] Step B. 5-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8- difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxamide: To a mixture of 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (500 mg, 1.0 equiv), (1- ((dimethylamino)methyl)cyclopropyl)methanol (399 mg, 3.0 equiv), 4Å molecular sieve (100 mg, 1.0 equiv) in DMF (5 mL) was added DIEA (399 mg, 3.0 equiv), and then the mixture was stirred at 110 °C for 36 hrs. The reaction mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (200 mg, 28% yield) as white solid; LCMS (ESI, M+1, M+3): m / z = 578.1, 580.1. [000340] Step C. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-bromo-2-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (180 mg, 1.0 equiv), 5-ethyl- 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (197 mg, 2.0 equiv), Cs2CO3 (304 mg, 1.5 M in water, 3 equiv) and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (22.7 mg, 0.1 equiv) in CPME (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred a 60 °C for 12 hours under N2 atmosphere. The mixture was diluted with water (10 mL), filtered and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (115 mg, 51% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.73 - 7.65 (m, 2H), 7.30 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.00 - 6.96 (m, 1H), 6.69 - 6.65 (m, 1H), 5.20 - 5.05 (m, 2H), 4.57 - 4.52 (m, 2H), 4.36 - 4.24 (m, 4H), 3.35 (m, 3H), 3.09 - 3.06 (m, 3H), 2.61 - 2.53 (m, 1H), 2.46 (br d, J = 6.4 Hz, 2H), 2.43 - 2.36 (m, 3H), 2.33 - 2.30 (m, 6H), 0.82 - 0.77 (m, 3H), 0.73 - 0.69 (m, 2H), 0.54 - 0.49 (m, 2H); LCMS (ESI, M+1): m / z = 688.4. [000341] EXAMPLE 56  4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol[000342] Step A. 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoro-quinazoline (0.5 g, 1.0 equiv) and DIPEA (411 mg, 2.0 equiv) in DCM (10 mL) was added 6-methyl-1,4-oxazepan-6-ol (198 mg, 0.95 equiv) in DCM (5 mL) dropwise at 0 °C. The mixture was stirred at 15 °C for 1 hours. The mixture was diluted with H2O (20 mL) at 0 °C and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified with column chromatography [SiO2, petroleum ether / ethyl acetate=2 / 1 to 1 / 1] to afford the title compound (0.5 g, 76% yield) as light yellow solid; LCMS (ESI, M+1, M+3): m / z = 408.0, 410.0. [000343] Step B. 4-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8- difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a mixture of 4-(7-bromo-2-chloro-6,8- difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.5 g, 1.0 equiv) and (1- ((dimethylamino)methyl)cyclopropyl)methanol (316 mg, 2.0 equiv) in DMSO (2.5 mL) was added DIPEA (319 mg, 2.0 equiv) and 4Å molecular sieve (30 mg). The mixture was stirred at 90 °C for 13 hours. The reaction mixture was filtered. The filtrate was purified with reversed phase flash [water (FA, 0.1%) / acetonitrile = 3 / 2] to afford the title compound (0.35 g, 50% yield) as light- yellow solid; LCMS (ESI, M+1, M+3): m / z = 501.1, 503.1.  [000344] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 4-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8- difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.35 g, 1.0 equiv) and 5-ethyl-6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (255 mg, 1.3 equiv) in methoxycyclopentane (6.25 mL) was K3PO4 (1.5 M in H2O, 1.23 mL, 3.0 equiv) and Ad2nBuP- Pd-G3 (45 mg, 0.1 equiv) under N2 atmosphere. The mixture was stirred at 80 °C for 3 hours. The mixture was diluted with H2O (2 mL) and extracted with ethyl acetate (4 × 3 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified with reversed phase flash [water (FA, 0.1%) / acetonitrile=13 / 7] and prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (NH4HCO3)-ACN; B%: 59%-89%, 10 minutes] to afford the tittle compound (156 mg, 40% yield, 0.26FA) as white solid;1H NMR (400 MHz, methanol-d4) δ = 8.16-8.09 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.01-6.96 (m, 1H), 4.46-4.42 (m, 1H), 4.41-4.35 (m, 3H), 4.04-3.97 (m, 2H), 3.93-3.84 (m, 2H), 3.38-3.64 (m, 2H), 2.69-2.54 (m, 3H), 2.49 (s, 6H), 2.45-2.36 (m, 1H), 1.27-1.25 (m, 3H), 0.85-0.77 (m, 5H), 0.63-0.58 (s, 2H); LCMS (ESI, M+1): m / z = 611.4. [000345] EXAMPLE 57(1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol  [000346] Step A. (1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol: To a mixture of 4-[2-[[1- [(dimethylamino)methyl]cyclopropyl]methoxy]-6,8-difluoro-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl]-5-ethyl-6-fluoro-naphthalen-2-ol (117 mg, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (51.35 mg, 2.0 equiv) in MeCN (5 mL) and DMF (5 mL) was added K3PO4 (128 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hrs. The mixture was filtered and purified by prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water (FA)-ACN]; B%: 36%-56%, 2min) to afford the title compound (27 mg, 22% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 7.59 - 7.52 (m, 1H), 7.43 (br d, J = 10.0 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.21 - 7.13 (m, 1H), 7.10 - 6.94 (m, 1H), 4.91 (br d, J = 11.6 Hz, 1H), 4.75 - 4.71 (m, 1H), 4.53 - 4.37 (m, 1H), 4.33 (br s, 2H), 4.21 - 3.95 (m, 1H), 3.76 - 3.54 (m, 1H), 3.37 - 3.28 (m, 1H), 2.99 - 2.90 (m, 1H), 2.89 - 2.72 (m, 1H), 2.70 - 2.59 (m, 6H), 2.58 - 2.33 (m, 2H), 2.33 - 2.23 (m, 2H), 2.21 - 2.04 (m, 1H), 1.83 - 1.70 (m, 2H), 1.35 - 1.01 (m, 1H), 0.87 - 0.75 (m, 4H), 0.71 - 0.62 (m, 2H); LCMS (ESI, M+1): m / z = 607.3. [000347] EXAMPLE 58 (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone[000348] Step A. (5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone: To a solution of 7-bromo-2,4- dichloro-6,8-difluoroquinazoline (500 mg, 1.0 equiv) in DCM (4 mL) were added DIEA (1.65 g, 8.0 equiv) and pyrrolidin-1-yl(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)methanone (560 mg, 1.5 equiv). The mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to dichloromethane: methanol=10:1) to afford the title compound (460 mg, 56% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 510.8, 512.8. [000349] Step B. (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)(pyrrolidin-1-yl)methanone: To a solution of (5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4- yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone (240 mg, 1.0 equiv) in DMAc (5 mL) was added CsF (712 mg, 10 equiv) and ((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methanol (373 mg, 5.0 equiv). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered and purified by prep-HPLC [column: YMC Triart C18250 × 50  mm × 7 µm; mobile phase: (water (NH3•H2O)-ACN); B%: 47%-77% over 20 min] to afford the title compound (70 mg, 23% yield) as white solid; LCMS (ESI, M+1, M+3): m / z = 634.3, 636.3. [000350] Step C. (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone: To a solution of (5-(7-bromo- 6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone (60 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (89.7 mg, 3.0 equiv) in methoxycyclopentane (1 mL) were added K3PO4 (60.2 mg, 3 equiv) and Ad2nBuP-Pd-G3 (6.89 mg, 0.1 equiv). The mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 1.5 hours under N2 atmosphere. The reaction mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; A: water (10mM HCOOH), B: ACN, B%: 24%-54% over 10 min] to afford the title compound (4.17 mg, 5.9 % yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.80-7.64 (m, 2H), 7.33-7.20 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.79 (s, 1H), 5.46-5.26 (m, 1H), 5.21-5.06 (m, 2H), 4.58-4.51 (m, 2H), 4.38-4.24 (m, 4H), 3.93 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H), 3.43-3.36 (m, 2H), 3.19- 3.06 (m, 2H), 2.64-2.52 (m, 1H), 2.48-2.35 (m, 4H), 2.34-2.26 (m, 1H), 2.24-2.16 (m, 1H), 2.12- 2.03 (m, 2H), 2.00-1.90 (m, 5H), 0.80 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 744.4 [000351] EXAMPLE 595-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide  [000352] Step A. 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N-isopropyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4- dichloro-6,8-difluoroquinazoline (300 mg, 1.0 equiv), 4 Å molecular sieve (10 mg) in DCM (0.5 mL) was added DIEA (370 mg, 3.0 equiv) and N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (297 mg, 1.2 equiv, HCl). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (201 mg, 38% yield) as yellow solid. LCMS (ESI, M+1, M+3): m / z = 498.8, 500.8. [000353] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4- yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (180 mg, 1.0 equiv) and 4 Å molecular sieve (10 mg) in dioxane (1 mL) was added DIEA (186 mg, 4.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (287 mg, 5.0 equiv). The mixture was stirred at 90 °C for 5 hours. The mixture was filtered to give a residue. The residue was purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (60 mg, 26% yield) as yellow solid. LCMS (ESI, M+1, M+3): m / z = 621.8, 623.8. [000354] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-  bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (45.0 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (68.6 mg, 3.0 equiv) and K3PO4 (46.0 mg, 3.0 equiv) in methoxy-cyclopentane (0.5 mL) was added Ad2nBuP-Pd-G3 (5.30 mg, 0.1 equiv). The mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 90 °C for 1.5 hours under N2 atmosphere. The mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 µm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10min) to afford the title compound (9.4 mg, 17 % yield, FA) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.77 (d, J = 10.0 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30-7.23 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.77 (s, 1H), 5.48-5.34 (m, 1H), 5.20-5.04 (m, 2H), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 2H), 4.34-4.28 (m, 2H), 4.16 (td, J = 6.8, 13.2 Hz, 1H), 3.52-3.46 (m, 2H), 3.22-3.13 (m, 2H), 2.61- 2.50 (m, 1H), 2.47-2.30 (m, 5H), 2.29-2.10 (m, 4H), 2.02-1.94 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H), 0.80 (t, J = 7.6 Hz, 3H). LCMS (ESI, M+1): m / z = 732.5. [000355] EXAMPLE 604-(4-(dimethylamino)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [000356] Step A: 4-(4-(dimethylamino)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: A mixture of 4- (6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol in N-methylmethanamine (1 M, 1.64 mL, 5.0 equiv) was stirred at 60 °C for 12 hours. The mixture was concentrated and purified with reversed-phase HPLC(column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 55%-85% over 8 min) to afford the title compound (41.9 mg, 23% yield) as yellow solid; SFC: "Column: Chiralpak IC-350 × 4.6 mm I.D., 3 µm Mobile phase: Phase A for CO2, and Phase B for IPA (0.05%DEA); Gradient elution: 40% IPA (0.05% DEA) in CO2 Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar.1H NMR (400 MHz, DMSO-d6) δ = 9.97 (s, 1H), 7.91 (d, J = 10.4 Hz, 1H), 7.78 (dd, J = 6.0, 8.4 Hz, 1H), 7.42-7.32 (m, 2H), 7.05-6.98 (m, 1H), 5.44-5.11 (m, 1H), 4.10 (dd, J = 4.0, 10.4 Hz, 1H), 4.04-3.96 (m, 1H), 3.45-3.35 (m, 6H), 3.15-2.98 (m, 3H), 2.83-2.80 (m, 1H), 2.47-2.28 (m, 2H), 2.19-1.95 (m, 3H), 1.88-1.69 (m, 3H), 0.75 (t, J = 7.2 Hz, 3H), LCMS (ESI, M+1): m / z = 555.3. [000357] EXAMPLE 614-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol  [000358] Step A. 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)yl)methoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol: To a solution of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol (200 mg, 1.0 equiv) and 5,6,7,8-tetrahydro-4H-triazolo[1,5- a][1,4]diazepine (90.7 mg, 2.0 equiv) in DMF (0.5 mL) was added DIEA (127 mg, 3.0 equiv). The mixture was stirred at 90 °C for 12 hours. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified with reversed phase flash [Waters Xbridge 150 × 25mm × 5um; mobile phase: A:water (NH4HCO3); B: ACN; B%: 40%-70% over 8.5min] to afford the title compound (7.74 mg, 3.4% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.83-7.76 (m, 1H), 7.72-7.63 (m, 2H), 7.31- 7.20 (m, 2H), 7.00-6.95 (m, 1H), 5.39-5.09 (m, 3H), 4.79-4.71 (m, 2H), 4.44-4.27 (m, 2H), 4.23-4.12 (m, 2H), 3.29-3.15 (m, 3H), 3.07-2.96 (m, 1H), 2.63-2.50 (m, 1H), 2.46-2.34 (m, 3H), 2.31-2.07 (m, 3H), 2.04-1.86 (m, 3H), 0.84-0.75 (m, 3H); LCMS (ESI, M+1): m / z = 648.4 [000359] EXAMPLE 62  7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione[000360] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7- diazaspiro[4.5]decane-1,3-dione: To a mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol (200 mg, 1.0 equiv), 2,7-diazaspiro[4.5]decane-1,3-dione (66.2 mg, 1.2 equiv) and 4Å molecular sieve (50.0 mg, 1.0 equiv) in MeCN (1.0 mL) and DMF (1.0 mL) was added K3PO4 (209 mg, 3.0 equiv). The mixture was stirred at 40 °C for 12 hrs. The reaction mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 150 × 25mm × 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 44%-74%,9min] and lyophilized to afford the title compound (16.8 mg, 7% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.67 (dd, J = 6.0, 8.8 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.31 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.00 - 6.97 (m, 1H), 5.40 - 5.21 (m, 1H), 4.42 (br t, J = 12.0 Hz, 1H), 4.34 - 4.13  (m, 3H), 3.67 - 3.53 (m, 2H), 3.27 - 3.11 (m, 3H), 3.04 - 2.91 (m, 2H), 2.72 - 2.64 (m, 1H), 2.61 - 2.52 (m, 1H), 2.47 - 2.37 (m, 1H), 2.24 (br s, 1H), 2.22 - 2.07 (m, 3H), 2.06 - 1.83 (m, 6H), 0.86 - 0.73 (m, 3H); LCMS (ESI, M+1): m / z = 678.5. [000361] EXAMPLE 635-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [000362] EXAMPLE 645-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide  [000363] Step A: 5-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo diazepine-2-carboxamide and 5-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [IPA-ACN]; B%: 40%-40% over 7.0 min), and then purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; Phase A: water (NH4HCO3); Phase B: ACN, B%: 48%-78% over 10 min) to afford two peaks. [000364] Example 63 (124 mg, 13% yield) as white solid; column: Chiralpak IC-350 × 4.6 mm I.D., 3 μm, mobile phase: [40% IPA+ACN (0.05% DEA)] in CO2, flow rate: 3mL / min, detector: 220 nm, tR: 1.289 min;1H NMR (400 MHz, DMSO-d6) δ 7.78-7.63 (m, 2H), 7.34-7.19 (m, 2H), 6.98 (d, J = 2.8 Hz, 1H), 6.70 (s, 1H), 5.40-5.21 (m, 1H), 5.20-5.04 (m, 2H), 4.58-4.49 (m, 2H), 4.41-4.08 (m, 4H), 3.37-3.33 (m, 3H), 3.27-3.13 (m, 3H), 3.12-3.05 (m, 3H), 3.04-2.96 (m, 1H), 2.67-2.51 (m, 1H), 2.45-2.31 (m, 3H), 2.27-2.06 (m, 3H), 2.05-1.82 (m, 3H), 0.86-0.73 (m, 3H); LCMS (ESI, M+1): m / z = 718.5. [000365] Example 64 (148 mg, 16% yield) as white solid; column: Chiralpak IC-350 × 4.6 mm I.D., 3 μm, mobile phase: phase A: 40% IPA, phase B: ACN (0.05% DEA) in CO2, flow rate: 3 mL / min, detector: 220 nm, tR: 1.979 min;1H NMR (400 MHz, DMSO-d6) δ 7.77-7.64 (m, 2H), 7.33-7.20 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H), 5.40-5.22 (m, 1H), 5.21-5.06 (m, 2H), 4.64-4.43 (m, 2H), 4.40-4.15 (m, 4H), 3.35 (s, 3H), 3.27-3.13 (m, 3H), 3.08 (s, 3H), 3.04-2.97  (m, 1H), 2.63-2.51 (m, 1H), 2.45-2.33 (m, 3H), 2.25-2.05 (m, 3H), 2.04-1.84 (m, 3H), 0.80 (t, J = 7.6 Hz, 3H); LCMS [ESI, M+1]: m / z = 718.5. [000366] EXAMPLE 65(S)-4-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol [000367] EXAMPLE 66(S)-4-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol  [000368] Step A. (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (12.0 g, 1.0 equiv), 4Å molecular sieves (2 g) and DIEA (19.8 g, 4.0 equiv) in DCM (100 mL) was added a solution of (S)-6-methyl-1,4-oxazepan-6-ol (5.77 g, 0.9 equiv, HCl) in DCM (20 mL) at 0 °C. The solution was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum and triturated with petroleum ether : ethyl acetate = 5:1 at 15oC for 15 minutes to afford the tittle compound (9.6 g, 56% yield) as yellow solid. LCMS (ESI, M+1, M+3): m / z = 408.0, 410.0. [000369] Step B. (S)-4-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: A mixture of (S)-4-(7- bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.20 g, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (16 mL) was stirred at 90 °C for 36 hours. The solution was diluted with MeOH (50 mL) and purified by reversed phase flash (C18, 0.1% formic acid condition) to afford the title compound (7.8 g, 3 batches, 57% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 531.0, 533.2. [000370] Step C. (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol: A mixture of (S)-4-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (7.50 g, 1.0 equiv), 5- ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (5.80 g, 1.3 equiv),  Ad2nBuP-Pd-G3 (1.03 g, 0.1 equiv) and K3PO4 (1.5 M in water, 28.2 mL, 3.0 equiv) in methoxycyclopentane (90 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hours under N2 atmosphere. The mixture was diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated and purified by reversed phase flash [C18, 0.1% formic acid condition] to afford the title compound (6.3 g, 48% yield) as yellow solid; SFC condition: Chiralcel OJ-350×4.6mm I.D., 3um; Mobile phase: Phase A: CO2, Phase B MeOH(0.05%DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mL / min;Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar; LCMS (ESI, M+1): m / z = 641.3. [000371] Step D. (S)-4-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol and (S)-4-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4- oxazepan-6-ol: The title compounds were separated by SFC (DAICEL CHIRALCEL OJ (250 mm 50 mm,10 μm); mobile phase A: water, B:(0.1% NH3•H2O in MeOH), B%: 30% - 30% over 2.5 min) to afford two peaks. [000372] Example 65 (723 mg, 10% yield). SFC condition: Chiralcel OJ-350×4.6mm I.D., 3 um; Mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar;1H NMR (400 MHz, methanol-d4) δ = 8.08 (dd, J = 1.6, 10.4 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 5.42-5.19 (m, 1H), 4.47-4.40 (m, 1H), 4.37-4.18 (m, 3H), 4.10-3.96 (m, 2H), 3.91-3.80 (m, 2H), 3.71-3.59 (m, 2H), 3.29-3.13 (m, 3H), 3.05-2.97 (m, 1H), 2.64-2.53 (m, 1H), 2.49-2.40 (m, 1H), 2.38-2.24 (m, 1H), 2.23-2.08 (m, 2H), 2.03-1.82 (m, 3H), 1.24 (s, 3H), 0.82 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+3): m / z = 641.3. [000373] Example 66 (744 mg, 10% yield). SFC condition: Chiralcel OJ-350×4.6mm I.D., 3 um; Mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar;1H NMR (400 MHz, METHANOL-d4) δ = 8.11 (dd, J = 1.2, 10.4 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.98 (d, J = 2.4  Hz, 1H), 5.41–5.17 (m, 1H), 5.52–4.44 (m, 1H), 4.37–4.19 (m, 3H), 4.06–3.95 (m, 2H), 3.88–3.78 (m, 2H), 3.73–3.57 (m, 2H), 3.28–3.13 (m, 3H), 3.05–2.96 (m, 1H), 2.61–2.48 (m, 1H), 2.45–2.35 (m, 1H), 2.35–2.16 (m, 2H), 2.16–2.07 (m, 1H), 2.03–1.82 (m, 3H), 1.26 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H)); LCMS [ESI, M+1]: m / z = 641.3. [000374] EXAMPLE 67(1R,5R,6R)-3-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol [000375] EXAMPLE 68(1R,5R,6R)-3-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol  [000376] Step A: (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol: To a mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol (1.0 g, 1.0 equiv), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (625.97 mg, 3.0 equiv) in DMF (2 mL) was added DIEA (636 mg, 3.0 equiv) and 4Å molecular sieve (0.5 g). The mixture was at 60 °C for 12 hours. Water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reversed phase flash [C18, 0.1% formic acid condition] to afford the title compound (0.82 g, 70% yield) as yellow solid; LCMS (ESI, M+1): m / z = 637.5. [000377] Step B: (1R,5R,6R)-3-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol and (1R,5R,6R)-3-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-  3-azabicyclo[3.2.1]octan-6-ol: The title compounds were separated by SFC (column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water( NH4HCO3)-ACN]; B%: 57%-87% over 8 min) to afford two peaks. [000378] Example 67 (179 mg, 21% yield) as yellow solid. SFC: 100% ee, "Column: Chiralpak IC-350 × 4.6 mm I.D., 3 µm Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar".1H NMR (400 MHz, methanol-d4) δ = 8.05-7.92 (m, 1H), 7.67 (dd, J = 6.0, 8.4 Hz, 1H), 7.36-7.19 (m, 2H), 6.97 (d, J = 2.0 Hz, 1H), 5.39-5.21 (m, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.69-4.62 (m, 1H), 4.37-4.16 (m, 3H), 3.55-3.52 (m, 1H), 3.48-3.42 (m, 1H), 3.23-3.19 (m, 3H), 3.04-2.98 (m, 1H), 2.62-2.55 (m, 1H), 2.47-2.31 (m, 3H), 2.31-2.10 (m, 5H), 1.98-1.75 (m, 4H), 1.55-1.42 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 637.3. [000379] Example 68 (179 mg, 21% yield) as yellow solid. SFC: 98.9% ee, Column: Chiralpak IC-350 × 4.6 mm I.D., 3 µm Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar".1H NMR (400 MHz, methanol-d4) δ = 8.08-7.93 (m, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.37-7.16 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 5.40-5.20 (m, 1H), 4.76-4.54 (m, 2H), 4.40-4.15 (m, 3H), 3.57 (d, J = 12.0 Hz, 1H), 3.49-3.41 (m, 2H), 3.25-3.16 (m, 2H), 3.08-2.95 (m, 1H), 2.62-2.51 (m, 1H), 2.50-2.29 (m, 3H), 2.28-2.11 (m, 4H), 1.99-1.77 (m, 4H), 1.66-1.58 (m, 1H), 1.57-1.43 (m, 1H), 0.80 (t, J = 8 Hz, 3H); LCMS (ESI, M+1): m / z = 637.4. [000380] EXAMPLE 69 (R)-1-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol [000381] EXAMPLE 70(R)-1-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000382] Step A. (R)-1-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol and (R)-1-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol: The title compounds were separated by SFC [condition: column: DAICEL CHIRALPAK AD (250mm × 50mm,10um); mobile phase: [0.1%NH3H2O IPA]; B%: 55%- 55%,4.1minutes] to afford two peaks. [000383] Example 69 (6.85 g, 20% yield) as a yellow solid;1H NMR (400 MHz, methanol- d4) δ = 7.80 (d, J = 9.6 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 5.44 - 5.15 (m, 1H), 4.34 - 4.18 (m, 3H), 4.05 (br d, J = 13.2 Hz, 1H), 3.46 - 3.35 (m, 2H), 3.28 - 3.13 (m, 3H), 3.06 - 2.95 (m, 1H), 2.63 - 2.51 (m, 1H),  2.47 - 2.11 (m, 5H), 2.03 - 1.71 (m, 6H), 1.29 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 625.5. [000384] Example 70 (6.02 g, 18% yield) as a yellow solid;1H NMR (400 MHz, methanol- d4) δ = 7.76 (br d, J = 8.8 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 5.45 - 5.16 (m, 1H), 4.33 - 4.15 (m, 3H), 4.05 (br d, J = 13.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.29 - 3.12 (m, 3H), 2.97-3.03 (m, 1H), 2.63 - 2.50 (m, 1H), 2.45 - 2.10 (m, 5H), 2.02 - 1.70 (m, 6H), 1.25 (s, 3H), 0.80 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 625.3. [000385] EXAMPLE 715-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol[000386] Step A. 6-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6- azaspiro[3.5]nonane: To a mixture of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (300 mg, 1.0 equiv) and 1-oxa-8-azaspiro[3.5]nonane; oxalic acid (349 mg, 1.0 equiv) in DCM (10 mL) was added DIEA (393 mg, 3.0 equiv). The reaction mixture was stirred at -40 °C for 2 hours under nitrogen atmosphere. The mixture was concentrated and purified by flash silica gel chromatography [SiO2, Petroleum ether / Ethyl acetate = 3 / 1] to afford the title compound (300 mg, 69% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 7.76 (d, J = 9.2 Hz, 1H), 7.55 (dd, J = 6.4, 8.8 Hz, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.25 (d, J = 13.2 Hz, 1H), 4.03 (td, J  = 4.4, 13.2 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.41 (ddd, J = 2.8, 9.6, 13.2 Hz, 1H), 2.43 (t, J = 8.0 Hz, 2H), 2.32-2.18 (m, 1H), 2.10-1.97 (m, 1H), 1.93-1.84 (m, 1H), 1.83-1.73 (m, 1H); LCMS (ESI, M+1): m / z = 388.0. [000387] Step B. 6-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: A mixture of 8-(7-bromo-2-chloro-8- fluoro-quinazolin-4-yl)-1-oxa-8-azaspiro[3.5]nonane (110 mg, 1.0 equiv) and [(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (453 mg, 10 equiv) in DMSO (0.05 mL) was stirred at 90 °C for 12 hours under N2 atmosphere. The mixture was concentrated and purified with prep-HPLC [FA condition; column: Phenomenex Synergi C18 150 × 25mm × 10 µm; mobile phase: [water (FA)-ACN]; B%: 9%-39%, 10 minutes] to afford the title compound (75.0 mg, 50% yield) as yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.32 (s, 1H), 7.68 (dd, J = 1.2, 8.8 Hz, 1H), 5.47-5.29 (m, 1H), 4.57 (t, J = 7.6 Hz, 2H), 4.47 (t, J = 2.8 Hz, 2H), 4.14 (br dd, J = 4.4, 13.2 Hz, 2H), 4.09-3.97 (m, 3H), 3.76-3.58 (m, 4H), 3.42-3.29 (m, 2H), 3.13-3.05 (m, 1H), 2.41 (br s, 2H), 2.34 (br s, 1H), 2.23-2.17 (m, 1H), 2.09 (br d, J = 5.6 Hz, 2H), 1.91-1.83 (m, 1H), 1.81-1.73 (m, 1H); LCMS [ESI, M+1]: m / z = 511.0 [000388] Step C. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (37.2 mg, 1.2 equiv) and 6-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (50.0 mg, 1.0 equiv) in methoxycyclopentane (3.0 mL) and H2O (0.6 mL) were added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (7.10 mg, 0.1 equiv) and Cs2CO3 (96.0 mg, 3.0 equiv). The reaction mixture was degassed and purged with nitrogen for 3 times and stirred at 80 °C for 2 hours under N2 atmosphere. The mixture was concentrated and purified with prep-HPLC [column: Waters Xbridge 150 × 25mm × 5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 37%-67%, 9 minutes] to afford the title compound (13.5 mg, 25% yield, HCOOH salt) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.02-7.92 (m, 1H), 7.70-7.60 (m, 1H), 7.40-7.28 (m, 1H), 7.27- 7.18 (m, 2H), 6.96 (d, J = 2.0 Hz, 1H), 5.50-5.24 (m, 1H), 4.58 (br s, 2H), 4.43-4.31 (m, 2H), 4.25- 4.07 (m, 1H), 3.89-3.68 (m, 1H), 3.57-3.33 (m, 4H), 3.18-3.05 (m, 1H), 2.54-2.27 (m, 6H), 2.26-  2.16 (m, 2H), 2.08 (br s, 3H), 2.01-1.88 (m, 2H), 1.80 (ddd, J = 2.4, 4.0, 8.4 Hz, 1H), 0.78 (br t, J = 7.2 Hz, 3H); LCMS [ESI, M+1]: m / z = 619.1. [000389] EXAMPLE 727-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide[000390] Step A. 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline: To a solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (480 mg, 1.0 equiv) and (5- chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane (513 mg, 1.0 equiv) in DMAc (5 mL) was added CataCXium A Pd G3(72.5 mg, 0.1 equiv) under N2. The reaction mixture was stirred at 90 °C for 5 hours under N2 atmosphere. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The combined layers were washed with brine (40 mL), dried over sodium sulfate, concentrated and purified with reversed phase flash (C 18, 0.1% FA) to afford the title compound (140 mg, 30% yield) as colorless oil. [000391] Step B.7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-  triazaspiro[4.5]decane 2,2-dioxide: To a solution of 7-(8-chloro-7-fluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluor-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (60 mg, 1.0 equiv) and 2-thia-1,3,7- triazaspiro[4.5]decane 2,2-dioxide (53.2 mg, 3.5 equiv) in DMF (0.6 mL) were added 4Å molecular sieve (7 g) and potassium phosphate (33.8 mg, 2.0 equiv). The reaction mixture was stirred at 60 °C for 12 hours under N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and purified with prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10µm; A: water(FA);B: ACN, B%: 12%-42% over 2min) to afford the title compound (36.0 mg) as yellow solid (FA salt). 1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (br s, 1H), 8.01 - 7.90 (m, 1H), 7.78 (ddd, J = 2.0, 5.6, 9.2 Hz, 1H), 7.37 (dt, J = 1.6, 8.8 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.09 (s, 1H), 5.60 - 5.31 (m, 1H), 4.64 - 4.47 (m, 2H), 4.47 - 4.32 (m, 1H), 4.30 - 4.16 (m, 1H), 3.82 - 3.50 (m, 5H), 3.43 (d, J = 11.9 Hz, 1H), 3.29 - 3.19 (m, 2H), 2.64 - 2.36 (m, 2H), 2.36 - 2.27 (m, 1H), 2.25 - 2.13 (m, 2H), 2.12 - 1.96 (m, 3H), 1.95 - 1.81 (m, 2H); LCMS [ESI, M+1]: m / z = 689.1. [000392] EXAMPLE 73(3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone  [000393] Step A. (5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-chloro-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a solution of 7- bromo-2,4-dichloro-8-fluoroquinazoline (1.00 g, 1.0 equiv) and (3-chloro-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone(1.15 g, 1.2 equiv) in dichloromethane (10 mL) was added DIEA (1.31 g, 3.0 equiv). The reaction mixture was stirred at -40 °C for 0.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (4 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and slurried with acetonitrile (30 mL) at 20 °C for 20 minutes to afford the title compound (1.20 g, 64% yield) as white solid; LCMS (ESI, M+1): m / z = 545.0. [000394] Step B. (5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)(morpholino)methanone: A mixture of (5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3- chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (1.10 g, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (965 mg, 3.0 equiv) was stirred at 110 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (4 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (100 mg, 7.1% yield) as yellow solid; LCMS (ESI, M+1): m / z = 668.0. [000395] Step C. (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a mixture of (5-(7-bromo-8- fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (100 mg, 1.0  equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (71.1 mg, 1.5 equiv) and K3PO4 (95.5mg, 3.0 equiv) in methoxycyclopentane (1.0 mL) and H2O (0.3 mL) was added Ad2nBup-Pd-G3 (10.9 mg, 0.10 equiv) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (4 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 51%-81% over 10min] and prep-HPLC [Phenomenex C1875 × 30 mm × 3 µm; A: water (FA), B: ACN, B%: 18%-48% over 7min] to afford the title compound (54.2 mg, 46% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.92 (d, J = 8.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.38-7.34 (m, 1H), 7.28-7.19 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 5.53-5.33 (m, 1H), 5.21-5.03 (m, 2H), 4.47-4.30 (m, 6H), 3.75 (s, 4H), 3.67 (s, 4H), 3.65-3.40 (m, 3H), 3.26-3.15 (m, 1H), 2.61-2.31 (m, 6H), 2.30- 2.22 (m, 1H), 2.19-2.08 (m, 2H), 2.03 (s, 1H), 0.79-0.75 (m, 3H); LCMS (ESI, M+1): m / z =776.3. [000396] EXAMPLE 743-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [000397] Step A. 5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-chloro-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo- 2,4-dichloro-8-fluoroquinazoline (950 mg, 1.0 equiv) and 3-chloro-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (779 mg, 1.0 equiv) in dichloromethane (9 mL) was added DIEA (2.07 g, 5.0 equiv) at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and triturated with acetonitrile (10 mL) at 20 °C for 20 minutes, filtered and concentrated to afford the title compound (1.13 g, 69% yield) as white solid; LCMS (ESI, M+1): m / z = 503.1. [000398] Step B. 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: A mixture of 5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3- chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (500 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (792 mg, 5.0 equiv) was stirred at 110 °C for 12 hours. The reaction mixture was cooled to 20 °C and diluted with water (5 mL). The crude product was slurried with H2O (6 mL) at 20 °C for 20 minutes and triturated with acetonitrile (4 mL) at 20 °C for 20 minutes to afford the title compound (420 mg, 61% yield) as white solid; LCMS (ESI, M+1): m / z = 626.1. [000399] Step C. 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[ diazepine-2-carboxamide: To a mixture of 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)- 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (150 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen- 2-ol (114 mg, 1.5 equiv) and K3PO4 (153 mg, 3.0 equiv) in methoxycyclopentane (1.5 mL) and H2O (0.5 mL) was added Ad2nBuP-Pd-G3 (17.5 mg, 0.10 equiv). The reaction mixture was stirred at 90 °C for 2 hours under N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography  [C18, 0.1 % formic acid condition] and prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 46%-76% over 8 min] to afford the title compound (30.3 mg, 17% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.88 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 6.0, 9.2 Hz, 1H), 7.32 (dd, J = 6.8, 8.4 Hz, 1H), 7.28 - 7.17 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 5.44 - 5.24 (m, 1H), 5.22 - 5.03 (m, 2H), 4.52 - 4.40 (m, 2H), 4.40 - 4.29 (m, 2H), 4.25 (s, 2H), 3.49 - 3.34 (m, 1H), 3.29 - 3.17 (m, 2H), 3.11 (d, J = 12.4 Hz, 6H), 3.08 - 2.99 (m, 1H), 2.56 - 2.28 (m, 5H), 2.27 - 2.10 (m, 2H), 2.05 - 1.89 (m, 3H), 0.77 (dt, J = 3.2, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 734.2. [000400] EXAMPLE 755-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide[000401] Step A. 5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4- dichloro-8-fluoroquinazoline (840 mg, 1.0 equiv) and DIEA (1.10 g, 3.0 equiv) in dichloromethane (1.0 mL) was added N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-  carboxamide (214 mg, 2.0 equiv) at -40 °C. The reaction mixture was stirred at -40 °C for 0.5 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and triturated with acetonitrile (15 mL) to afford the title compound (1.10 g, 80% yield) as white solid; LCMS (ESI, M+1): m / z = 483.1. [000402] Step B. 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: A mixture of 5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)- N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (400 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (1.18 g, 10 equiv) was stirred at 90 °C for 12 hours. The reaction mixture was slurried with water (15mL) to afford the title compound (300 mg, 54% yield) as brown solid. [000403] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7-bromo-8- fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3- trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol(125 mg, 1.2 equiv) in methoxycyclopentane (2 mL) and water (0.5 mL) were added Ad2nBup-Pd-G3 (24.1 mg, 0.1 equiv) and Cs2CO3(323 mg, 3.0 equiv) under N2atmosphere. The reaction mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The mixture was quenched with H2O (5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 21%-51% over 8min] to afford the title compound (100 mg, 98% yield, HCOOH salt) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.56 - 8.50 (m, 1H), 7.92 - 7.82 (m, 1H), 7.70 - 7.58 (m, 1H), 7.38 - 7.28 (m, 1H), 7.27 - 7.17 (m, 2H), 6.98 - 6.88 (m, 1H), 5.49 - 5.27 (m, 1H), 5.21 - 5.01 (m, 2H), 4.51 - 4.42 (m, 2H), 4.41 - 4.23 (m, 4H), 3.60 - 3.36 (m, 3H), 3.22 - 3.15 (m, 1H), 3.15 - 3.11 (m, 3H), 3.11 - 3.05 (m, 3H), 2.52 - 2.27 (m, 6H), 2.25 - 2.05 (m, 6H), 2.03 - 1.87 (m, 1H), 0.84 - 0.67 (m, 3H); LCMS (ESI, M+1): m / z = 714.2.  [000404] EXAMPLE 76(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone[000405] Step A. (5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: To a solution of 7-bromo- 2,4-dichloro-6,8-difluoroquinazoline (880 mg, 1.0 equiv) and DIEA (1.10 g, 3.0 equiv) in dichloromethane (1 mL) was added (4-methylpiperazin-1-yl)(5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)methanone (775 mg, 1.1 equiv). The reaction mixture was stirred at -40 °C for 0.5 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and slurried with acetonitrile (15 mL) to afford the title compound (800 mg, 52% yield) as white solid; LCMS (ESI, M+1): m / z = 542.2. [000406] Step B. (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4- methylpiperazin-1-yl)methanone: A mixture of (5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-  yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone (400 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (1.18 g, 10 equiv) was stirred at 90 °C for 12 hours. The reaction mixture was concentrated and slurried with water (15mL) to afford the title compound (300 mg, 54% yield) as brown solid; LCMS (ESI, M+1): m / z = 665.1. [000407] Step C. (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: To a mixture of (5-(7- bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone (250 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-ol (143 mg, 1.2 equiv) in methoxycyclopentane (2 mL) and water (0.5 mL) were added Ad2nBup-Pd-G3 (41.1 mg, 0.15 equiv) and Cs2CO3 (368 mg, 3.0 equiv) under N2 atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was quenched with H2O (5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 10%-40% over 8min] to afford the title compound (90.0 mg, 96% yield, HCOOH salt) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 8.46 - 8.43 (m, 1H), 7.84 - 7.76 (m, 1H), 7.72 - 7.65 (m, 1H), 7.34 - 7.29 (m, 1H), 7.29 - 7.22 (m, 1H), 7.28 - 7.21 (m, 1H), 7.01 - 6.96 (m, 1H), 6.76 - 6.70 (m, 1H), 5.65 - 5.41 (m, 1H), 5.25 - 5.06 (m, 2H), 4.59 - 4.31 (m, 6H), 4.22 - 4.00 (m, 2H), 3.92 - 3.64 (m, 5H), 3.40 - 3.33 (m, 1H), 2.70 - 2.45 (m, 7H), 2.45 - 2.31 (m, 7H), 2.30 - 2.20 (m, 2H), 2.18 - 2.05 (m, 1H), 0.91 - 0.72 (m, 3H); LCMS (ESI, M+1): m / z = 773.2. [000408] EXAMPLE 77  4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-6- azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol[000409] Step A. 6-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1-oxa-6- azaspiro[3.5]nonane: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.50 g, 1.0 equiv) and 1-oxa-6-azaspiro[3.5]nonane (905 mg, 1.1 equiv, 0.5 oxalic acid) in DCM (15 mL) were added DIEA (2.47 g, 4.0 equiv) and 4Å molecular sieve (1.5 g). The reaction mixture was stirred at 0 °C for 15 mins. The mixture was filtered. The filtrate was concentrated and triturated with petroleum ether : ethyl acetate = 3:1 (10 V) at 25 °C for 30 mins to afford the title compound (1.50 g, 77.6% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.01 (dd, J = 1.6, 9.8 Hz, 1H), 4.39 (t, J = 7.8 Hz, 2H), 4.29 (br d, J = 13.6 Hz, 1H), 4.12-4.02 (m, 1H), 3.67 (d, J = 13.6 Hz, 1H), 3.32 (s, 1H), 2.42-2.28 (m, 2H), 2.15-2.05 (m, 1H), 1.88-1.75 (m, 2H), 1.73-1.61 (m, 1H), 1.32-1.20 (m, 1H). [000410] Step B. 6-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: A mixture of 6-(7-bromo-2-chloro- 6,8-difluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (500 mg, 1.0 equiv) and ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (197 mg, 1.0 equiv) was heated to 110 °C for 2 hours. The reaction mixture was concentrated and triturated with petroleum ether : ethyl acetate  =1:5 (3 mL) at 25 °C for 10 mins to afford the title compound (230 mg, 35% yield) as brown solid; LCMS (ESI, M+1): m / z = 527.1. [000411] Step C.6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6- azaspiro[3.5]nonane: To a mixture of 6-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (80.0 mg, 1.0 equiv), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (60.1 mg, 1.1 equiv) in DMF (5 mL) and H2O (1 mL) were Ad2nBuP Pd G3(cataCXium® A Pd G3) (11.1 mg, 0.1 equiv) and K3PO4 (96.6 mg, 3.0 equiv). The reaction mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over sodium sulfate, filtered, concentrated and purified by column chromatography [SiO2, DCM: MeOH=10 / 1] to afford the title compound (55 mg, crude) as yellow solid; LCMS (ESI, M+1): m / z = 681.3. [000412] Step D. 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2- ol: To a mixture of 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6- azaspiro[3.5]nonane (20.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TFA (770 mg, 229.8 equiv). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by addition of sat. NaHCO3 aqueous solution (20 mL) at 0°C, and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified with prep-HPLC [column: Phenomenex C1875*30 mm*3 µm; mobile phase: (water (FA)-CAN); B%: 20%-50%, 7 minutes] to afford the title compound (6.40 mg, 30.8% yield, HCOOH salt) as yellow solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 7.84 (t, J = 9.8 Hz, 1H), 7.68 (dd, J = 6.0, 9.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 5.41-5.21 (m, 1H), 4.66-4.52 (m, 2H), 4.48-4.36 (m, 1H), 4.35-4.21 (m, 2H), 4.21-4.09 (m, 1H), 3.65 (dd, J = 13.8, 19.6 Hz, 1H), 3.36 (br d, J = 2.3 Hz, 1H), 3.29-3.15 (m, 3H), 3.08-2.97 (m, 1H), 2.65-2.52 (m, 1H), 2.48 (t,  J = 7.9 Hz, 2H), 2.44-2.33 (m, 1H), 2.32-2.21 (m, 2H), 2.20-2.11 (m, 1H), 2.09-1.96 (m, 3H), 1.95- 1.85 (m, 2H), 1.85-1.74 (m, 1H), 0.86-0.76 (m, 3H); LCMS (ESI, M+1): m / z = 637.1. [000413] EXAMPLE 783-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000414] Step A. 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-chloro-N,N- dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7- bromo-2,4-dichloro-6,8-difluoro-quinazoline (1.20 g, 1.0 equiv) in dichloromethane (10 mL) was  added N-ethyl-N-propan-2-ylpropan-2-amine (4.78 mL, 5.0 equiv) and 3-chloro-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide hydrochloride (1.28 g, 1.2 equiv). The reaction mixture was stirred at -40 °C for 1 hour. The mixture was quenched with water (50ml) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (2.00 g, crude) as yellow solid. [000415] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-2-chloro-6,8-difluoro-quinazolin-4- yl)-3-chloro-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.00 g, 1.0 equiv) in DMSO (0.5 mL) was added [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (6.12 g, 10.0 equiv). The mixture was stirred at 90 °C for 48 hours. The mixture diluted with water (5 mL) extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed-phase flash (0.1% FA condition) to afford the title compound (292 mg, 9% yield) as yellow solid; LCMS (ESI, M+3): m / z = 644.3. [000416] Step C. 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7- bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (100 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen- 2-ol (73.8 mg, 1.5 equiv) and tripotassium phosphate (1.5 M in water, 0.25 mL, 3.0 equiv) in CPME (1.5 mL) was added CataCXium A Pd G3 (11.3 mg, 0.1 equiv). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 16 hours under N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed-phase flash (0.1% FA condition), followed by prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; A: water ( NH4HCO3), B:ACN; B%: 49%-79% over 9min] afford the title compound (7.99 mg, 7% yield) as a yellow solid.1H NMR (400 MHz,  METHANOL-d4) δ = 7.70 - 7.63 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.21 (s, 1H), 6.98 - 6.95 (m, 1H), 5.35 (br s, 1H), 5.12 - 5.06 (m, 2H), 4.50 - 4.45 (m, 2H), 4.35 - 4.26 (m, 2H), 4.24 - 4.19 (m, 2H), 3.22 (br s, 1H), 3.18 (br d, J = 2.8 Hz, 1H), 3.13 (s, 3H), 3.10 (s, 3H), 3.05 - 2.98 (m, 2H), 2.63 - 2.51 (m, 1H), 2.48 - 2.37 (m, 3H), 2.33 - 2.05 (m, 3H), 2.03 - 1.86 (m, 3H), 0.84 - 0.75 (m, 3H); LCMS (ESI, M+1): m / z =752.3. [000417] EXAMPLE 79(3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone[000418] Step A. (5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-chloro-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a solution of (3-  chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone hydrochloride (1.23 g, 1.2 equiv) in DCM (10 mL) was added DIEA (2.06 g, 5.0 equiv) and 7- bromo-2,4-dichloro-6,8-difluoro-quinazoline (1.00 g, 1.0 equiv) . The reaction mixture was stirred at -40 °C for 1 hour. The mixture was quenched with H2O (50ml) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (2.00 g, crude) as yellow oil; LCMS (ESI, M+1): m / z = 563.1. [000419] Step B. (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)(morpholino)methanone: To a solution of [5-(7-bromo-2-chloro-6,8-difluoro-quinazolin-4-yl)- 3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-morpholino-methanone (2.00 g, 1.0 equiv) in DMSO (2 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (5.66 g, 10 equiv). The reaction mixture was stirred at 90 °C for 2 days. The mixture was diluted with water (20 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed-phase flash (0.1% FA condition) to afford the title compound (843 mg, 32% yield) as yellow solid. LCMS (ESI, M+1): m / z = 686.2. [000420] Step C. (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a mixture of (5-(7- bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)(morpholino)methanone (100 mg, 1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-ol (69.2 mg, 1.5 equiv) and K3PO4 (1.5 M in water, 292 µL, 3.0 equiv) in CPME (1.5 mL) was added CataCXium A Pd G3 (10.6 mg , 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times and stirred at 90 °C for 5 hours under N2 atmosphere. The mixture was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed- phase flash (0.1% FA condition). The desired fractions were collected and neutralized with solid NaHCO3 concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with  DCM (3× 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC (column: Waters Xbridge 150 × 25mm × 5µm; A: [water (ammonia hydroxide)]; B: ACN, B%: 46%-76% over 9min) to afford the title compound (8.35 mg, 7% yield, HOOH salt) as white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.71 - 7.62 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 - 6.95 (m, 1H), 5.38 - 5.25 (m, 1H), 5.14 - 5.07 (m, 2H), 4.54 - 4.40 (m, 2H), 4.36 - 4.27 (m, 2H), 4.25 - 4.18 (m, 2H), 3.74 (s, 4H), 3.67 (s, 4H), 3.63 - 3.63 (m, 1H), 3.25 - 3.14 (m, 2H), 3.07 - 2.98 (m, 1H), 2.64 - 2.52 (m, 1H), 2.48 - 2.39 (m, 3H), 2.34 - 2.20 (m, 1H), 2.18 - 2.08 (m, 2H), 2.02 - 1.95 (m, 2H), 1.94 - 1.85 (m, 1H), 0.80 (dt, J = 2.8, 7.3 Hz, 3H); LCMS (ESI, M+1): m / z = 794.5. [000421] EXAMPLE 805-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide  [000422] Step A. 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N,3-trimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo- 2,4-dichloro-6,8-difluoroquinazoline (1.0 g, 1.0 equiv) and DIEA (617 mg, 1.5 equiv) in DCM (10 mL) were added a solution of N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (602 mg, 0.85 equiv) and DIEA (823 mg, 2.0 equiv) in DMF (3 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with brine (10 ml), dried over Na2SO4, concentrated purified with reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (1.2 g, 53% yield, 71% purity) as yellow solid; LCMS (ESI, M+1, M+3, M+5): m / z = 499.1, 501.1, 503.1. [000423] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4- yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (400 mg, 71% purity, 1.0 equiv) in DMSO (2 mL) was added ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (1.27 g, 14 equiv). The mixture was stirred at 90°C for 24 hours. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with brine (10 ml), dried over Na2SO4, concentrated and purified with reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (200 mg, 54% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 622.2, 624.2.  [000424] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 1.0 equiv) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2- ol (203 mg, 2.0 equiv) in methoxycyclopentane (2 mL) were added K3PO4 (1.5 M in H2O, 642 μL, 3.0 equiv) and CataCXium A Pd G3 (23.4 mg, 0.1 equiv). The mixture was stirred at 90 °C for 5 hours. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over Na2SO4, concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 18%-48% over 10 minutes] to afford the title compound (101 mg, 42% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.70 - 7.63 (m, 2H), 7.29 (d, J = 2.6 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 5.50 - 5.28 (m, 1H), 5.05 (br dd, J = 2.8, 8.1 Hz, 2H), 4.47 (br d, J = 6.7 Hz, 2H), 4.35 (br d, J = 2.6 Hz, 1H), 4.32 (br d, J = 11.1 Hz, 3H), 3.57 - 3.39 (m, 3H), 3.20 - 3.12 (m, 4H), 3.08 (s, 3H), 2.62 - 2.44 (m, 2H), 2.43 - 2.31 (m, 4H), 2.21 (br s, 1H), 2.18 (s, 3H), 2.15 - 2.05 (m, 2H), 2.03 - 1.91 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 732.4. [000425] EXAMPLE 815-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-  pyrazolo[1,5-a][1,4]diazepine-2-carboxamide[000426] Step A. 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,3-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4- dichloro-6,8-difluoroquinazoline (300 mg, 1.0 equiv) and DIEA (247 mg, 2.0 equiv) in dichloromethane (4.5 mL) was added a solution of N,3-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (298 mg, 1.5 equiv) in dichloromethane (3 mL) at - 40 °C. The reaction mixture was stirred at - 40 °C for 0.5 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated to afford the title compound (447 mg, crude) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 485.0, 487.0. [000427] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide: To a solution of 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4- yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (250 mg, 1.0 equiv) in DMSO (0.3 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methanol (410 mg, 5.0 equiv). The reaction mixture was stirred at 90 °C for 8 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified with reversed-phase flash [C18, 0.1% formic acid condition] to afford the title compound (37.0 mg, 11% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 608.0, 610.1. [000428] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 5-(7- bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4- yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (37.0 mg,  1.0 equiv), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (28.8 mg, 1.5 equiv) and K3PO4 (1.5 M in water, 122 μL, 3.0 equiv) in methoxycyclopentane (1 mL) was added cataCXium A Pd G3 (4.43 mg, 0.1 equiv). The reaction mixture was degassed and purged with N2 for 3 times and was stirred at 90 °C for 2 hours under N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25mm × 10 um; A, water (FA); B, ACN; B%: 17% - 47% over 10 mins] to afford the title compound (14.4 mg, 33% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL- d4) δ = 7.72 - 7.62 (m, 2H), 7.32 - 7.22 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 5.46 - 5.25 (m, 1H), 5.11 - 4.96 (m, 3H), 4.52 - 4.42 (m, 2H), 4.35 - 4.22 (m, 4H), 3.51 - 3.38 (m, 1H), 3.15 - 3.07 (m, 1H), 2.86 (s, 3H), 2.63 - 2.48 (m, 1H), 2.46 - 2.19 (m, 9H), 2.18 - 2.10 (m, 1H), 2.09 - 2.01 (m, 2H), 1.98 - 1.86 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =718.5. [000429] EXAMPLE 824-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(1-oxa-6- azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [000430] Step A. 1-(1-(((7-bromo-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6- yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: A mixture of 6-(7- bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (300 mg, 1.0 equiv) and (1-((dimethylamino)methyl)cyclopropyl)methanol (95.8 mg, 1.0 equiv) was heated to 110 °C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, concentrated and purified by reversed-phase MPLC [C18, 0.1% formic acid condition] to afford the title compound (350 mg, 90.2% yield) as a yellow liquid; LCMS (ESI, M+1): m / z = 499.0. [000431] Step B. 1-(1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8- difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N- dimethylmethanamine: To a mixture of 1-(1-(((7-bromo-6,8-difluoro-4-(1-oxa-6- azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (300 mg, 1.0 equiv) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (239 mg, 1.1 equiv) in DMF (5 mL) and H2O (1 mL) were added Ad2nBuP Pd G3 (cataCXium® A Pd G3 ) (43.9 mg, 0.1 equiv) and K3PO4 (384 mg, 3.0 equiv). The reaction was degassed and purged with nitrogen for 3 times, and then stirred at 100 °C for 12 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, concentrated and purified by reversed-phase MPLC [C18, 0.1% formic acid condition] to afford the title compound (160 mg, crude) as yellow liquid; LCMS (ESI, M+1): m / z = 651.5. [000432] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4- (1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 1-(1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-(1-oxa-6- azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (100 mg, 1.0 equiv) in DCM (3 mL) was added TFA (770 mg, 43.9 equiv). The reaction was stirred at 0 °C for 1 hour. The reaction mixture was quenched with sat. NaHCO3 aqueous solution (20 mL) at 0°C and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over sodium sulfate, filtered, concentrated and purified with prep-HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 18%-48%,  7 min) to afford the title compound (24.7 mg, 23.8% yield, HCOOH salt) as yellow solid.1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (s, 1H), 7.91-7.79 (m, 1H), 7.67 (dd, J = 6.0, 8.8 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.4 Hz, 1H), 7.04-6.88 (m, 1H), 4.62-4.51 (m, 1H), 4.49-4.32 (m, 3H), 4.14 (br t, J = 12.8 Hz, 1H), 4.07-3.92 (m, 1H), 3.76-3.60 (m, 1H), 3.37 (br d, J = 11.8 Hz, 1H), 2.70 (br d, J = 2.4 Hz, 2H), 2.61-2.41 (m, 8H), 2.38-2.20 (m, 2H), 2.16-1.97 (m, 1H), 1.96-1.85 (m, 1H), 1.80 (td, J = 4.3, 8.8 Hz, 1H), 0.88-0.75 (m, 5H), 0.61 (br s, 2H); LCMS (ESI, M+1): m / z = 607.2. [000433] EXAMPLE 83[000434] (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2-((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol[000435] Step A. tert-butyl (4-(6,8-difluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- ((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2- yl)carbamate: To a solution of (R)-1-(7-bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (450 mg, 1.0 equiv), (2-((tert- butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (423 mg, 1.5 equiv) in cyclopentyl methyl ether (6 mL) and were added [2-(2-aminophenyl)phenyl]palladium bis(1- adamantyl)butylphosphane methanesulfonate (65.9 mg, 0.1 equiv), tripotassium phosphate (576.14 mg) and water (1.36 mL). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 3 hrs. The mixture was diluted with water (5 mL) and extracted with  ethyl acetate (3 × 5 mL). The organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate (500 mg), concentrated and purified with reversed-phase flash (0.1% FA condition) to afford the title compound (450 mg, 70% yield); LCMS(ESI, M+1): m / z = 685.2. [000436] Step B. (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of tert-butyl (4-(6,8-difluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (100 mg, 1.0 equiv) in acetonitrile (1 mL) was added HCl / dioxane (4 M, 2 mL). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was dripped in to ice sodium hydrogen carbonate solution slowly at 0°C and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate (500 mg), concentrated and purified with prep- HPLC (column: Phenomenex luna C18150 × 25mm × 10µm; A: water(FA); B: ACN; B%: 14%- 44%,10min) and lyophilized to afford the title compound (17.8 mg, 20% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.73 (ddd, J = 1.6, 10.4, 18.4 Hz, 1H), 7.30 (ddd, J = 3.6, 5.2, 8.8 Hz, 1H), 6.99 (t, J = 8.8 Hz, 1H), 4.42 - 4.32 (m, 2H), 4.30 - 4.18 (m, 1H), 4.06 (br d, J = 13.0 Hz, 1H), 3.47 (dd, J = 5.6, 13.2 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.29 - 3.21 (m, 2H), 2.95 - 2.82 (m, 2H), 2.15 (td, J = 6.4, 12.4 Hz, 3H), 2.07 - 1.92 (m, 4H), 1.90 - 1.80 (m, 3H), 1.79 - 1.70 (m, 2H), 1.26 (d, J = 2.0 Hz, 3H); LCMS (ESI, M+1): m / z = 585.4. [000437] EXAMPLE 844-(4-(dimethylamino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8- dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol  [000438] Step A. methyl 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthoate: To a mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (20 g, 52.3 mmol, 1.00 eq), TEA (15.9 g, 157 mmol, 21.8 mL, 3.00 eq) in MeOH (100 mL) and DMSO (100 mL) was added Pd(dppf)Cl2(3.83 g, 5.23 mmol, 0.1 eq) in one portion at 20 °C under CO, then heated to 80 °C and stirred for 3 hours. The residue was poured into ice-water (500 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (200 mL × 2), the combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by a silica gel chromatography column (SiO2, Petroleum ether / Ethyl acetate=30 / 1 to 10 / 1) to give compound to give the title compound (12.0 g, 41.1 mmol, 78.5% yield) as light-yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.53 - 7.51 (m, 1H), 7.39 - 7.38 (d, J = 4.0 Hz, 1H), 7.26 - 7.25 (d, J = 4.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 5.19 (s, 2H), 3.90 (s, 3H), 3.43 (s, 3H), 2.81 - 2.78 (q, 2H), 1.18 – 1.14 (t, J = 8.0 Hz, 3H) [000439] Step B. (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methanol: To a mixture of methyl 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthoate (12.0 g, 41.1 mmol, 1.00 eq) in THF (120 mL) was added LiAlH4 (1.25 g, 32.8 mmol, 0.80eq) at 0 °C under N2. The mixture was stirred at 20 °C for 2 hrs. Add water (1.25 ml) to the reaction solution and stirred for 10 min,  add 15% NaOH (1.25 ml) and stirred for 10 min, then add water (4.00 ml) to the reaction solution and stirred for 10 min the mixture was filtered and concentrated in vacuum to give the title compound (9.66 g, crude) as yellow solid. [000440] Step C.8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthaldehyde: To a mixture of (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methanol (9.66 g, 36.6 mmol, 1.00 eq) and MnO2 (63.6 g, 731 mmol, 20.0 eq) in dichloromethane (100 mL) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 16 hrs. The mixture was filtered and concentrated in vacuum to give the title compound (9.00 g, crude) as black brown solid.1H NMR: (400 MHz, CDCl3). δ 10.6 (s, 1H), 7.65 - 7.64 (d, J = 4.0 Hz, 1 H), 7.63 - 7.59 (m, 1 H), 7.51 - 7.50 (d, J = 4.0 Hz, 1 H), 7.24 - 7.18 (m, 1 H), 5.22 (s, 2 H), 3.44 (s, 3 H), 2.97 - 2.95 (q, 2 H), 1.33 - 1.29 (t, J = 8.0 Hz, 3 H) [000441] Step D. methyl 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5- hydroxy-3-oxopentanoate: To a mixture of NaH (4.12 g, 103 mmol, 60% purity, 3.00 eq) in THF (50.0 mL) at 20 °C under N2, was added methyl 3-oxobutanoate (12.0 g, 103 mmol, 11.1 mL, 3.00 eq) at 20 °C. The mixture was stirred at 20 °C for 30 min, then was added n-BuLi (2.5 M, 41.2 mL, 3.00 eq) dropwise at -10 °C, the mixture was stirred at-10 °C for 30 min, then was added a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthaldehyde in THF (50.0 mL) drop-wise at -10 °C, the mixture was stirred at -10 °C for 2 hrs. The residue was poured into NH4Cl (200 mL) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 4 / 1) to give the title compound (10.0 g, 26.4 mmol, 77.0% yield) as yellow solid.1H NMR: EW34545-10-P1A (400 MHz, CDCl3). δ 7.72 - 7.71 (d, J = 4.0 Hz, 1 H), 7.63 - 7.59 (m, 1 H), 7.33 - 7.34 (d, J = 4.0 Hz, 1 H), 7.24 - 7.19 (m, 1 H), 6.15 - 6.12 (m, 1 H), 5.31 - 5.27 (m, 2H), 3.75 (s, 3 H), 3.54 (s, 2 H), 3.55 (s, 3 H), 3.37 - 3.31 (m, 1 H), 3.08 - 2.95 (m, 3 H), 2.80 - 2.73 (m,1 H), 1.34 - 1.30 (t, J = 8.0 Hz, 3H) [000442] Step E. methyl 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxo- 3,4-dihydro-2H-pyran-5-carboxylate: To a mixture of methyl 5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-5-hydroxy-3-oxopentanoate (5.00 g, 13.2 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added DMF-DMA (1.89 g, 15.7 mmol, 2.11 mL, 1.20 eq) in one  portion at 20 °C under N2. The mixture was stirred at 20 °C for 1 hr. Then was added BF3.Et2O (2.44 g, 17.2 mmol, 2.12 mL, 1.30 eq) at 20 °C, the mixture was stirred at 20 °C for 2 hrs. The residue was poured into ice-water (50.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (20.0 mL × 2), the combined organic phase was washed with brine (20.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 5 / 1) to give the title compound (4.30 g, 11.1 mmol, 83.8% yield) as yellow oil. LCMS: RT = 0.935 min, Hz = 389.2 [M+H]+[000443] Step F. methyl 6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4- oxotetrahydro-2H-pyran-3-carboxylate: To a mixture of methyl 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-oxo-3,4-dihydro-2H-pyran-5-carboxylate (3.00 g, 7.72 mmol, 1.00 eq) in THF (30.0 mL) at 20 °C under N2, then was added L-selectride (1 M, 11.6 mL, 1.50 eq) drop-wise at -70 °C. The mixture was stirred at -70 °C for 2 hrs. The residue was poured into NH4Cl (100 mL) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1) to give the title compound (1.00 g, 2.56 mmol, 33.1% yield) as white solid.1H NMR: (400 MHz, CDCl3), δ 7.56 - 7.54 (m, 2 H), 7.30 - 7.29 (d, J = 4.0 Hz, 1 H), 7.14 - 7.11 (m, 1 H), 5.59- 5.53 (m, 1 H), 5.21 (s, 2 H), 5.46 - 5.45 (m, 1 H), 4.42 - 4.37 (m, 1 H), 3.75 (s, 3 H), 3.44 (s, 3 H), 3.17 - 3.24 (m, 1 H), 2.78 - 2.71 (m, 1 H), 2.64 - 2.60 (m, 2 H), 2.56 - 2.32 (m, 2 H), 1.27 - 1.25 (m, 3H). [000444] Step G. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)- 7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-ol: To a mixture of methyl 6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-oxotetrahydro-2H-pyran-3-carboxylate (1.10 g, 2.82 mmol, 1.00 eq) in MeOH (10.0 mL) was added CH3ONa (5 M, 2.82 mL, 5.00 eq) and methyl carbamimidothioate sulfate (784 mg, 2.82 mmol, 1.00 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 16 hrs. The residue was poured into ice-water (20.0 mL) and stirred for 30 min. The pH was adjusted to around 3 by progressively adding 1M HCl, the aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with brine (10.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was  purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 4 / 1) to give the title compound (500 mg, 1.16 mmol, 31.7% yield) as white solid. LCMS: EW34545-18-P1A, RT = 0.965 min, [M+H]+= 431.2. [000445] Step H. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)- 7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate: To a mixture of 7-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-4-ol (500 mg, 1.16 mmol, 1.00 eq) and TEA (353 mg, 3.48 mmol, 3.00 eq) in dichloromethane (5.00 mL) was added Tf2O (492 mg, 1.74 mmol, 1.50 eq) at -40 °C under N2. The mixture was stirred at 20 °C for 1 hr. The residue was poured into ice-water (20.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (20.0 mL × 2), the combined organic phase was washed with brine (10.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Methyl Tertiary Butyl Ether) to give the title compound (650 mg, 924 umol) as yellow oil. LCMS: RT = 1.166 min, [M+H]+= 563.2 [000446] Step I.7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2- (methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: To a mixture of Me2NH (113 mg, 1.39 mmol, 1.20 eq, HCl) and DIEA (448 mg, 3.47 mmol, 3.00 eq) in THF (6.50 mL) was added 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (650 mg, 1.16 mmol, 1.00 eq) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 16 hrs. The residue was poured into ice-water (20.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (5.00 mL × 2), the combined organic phase was washed with brine (5.00 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 4 / 1) to give compound 16 (350 mg, 765 umol, 66.2% yield) as yellow oil. LCMS: RT = 0.876 min, [M+H]+= 458.2. [000447] Step J.7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2- (methylsulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: To a mixture of 7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2-(methylthio)-7,8-dihydro-5H- pyrano[4,3-d]pyrimidin-4-amine (350 mg, 765 umol, 1 eq) and ethyl acetate (5.00 mL) was added m-CPBA (388 mg, 1.91 mmol, 85% purity, 2.50 eq) in one portion at 20 °C under N2. The mixture  was stirred at 20 °C for 1 hr. The residue was poured into Na2SO3 (20.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (5.00 mL × 2), the combined organic phase was washed with brine (5.00 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1) to give the title compound (330 mg, 674 umol, 88.1% yield) as white solid. [000448] Step K.7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-4-amine: To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (52.0 mg, 327 umol, 1.60 eq) and t-BuONa (39.3 mg, 409 umol, 2.00 eq) in THF (1.00 mL) was added solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N- dimethyl-2-(methylsulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (100 mg, 204 umol, 1.00 eq) in THF (1.00 mL) drop-wise at 0°C under N2. The mixture was stirred at 20 °C for 1 hr. The residue was poured into water (20.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (5.00 mL × 2), the combined organic phase was washed with brine (5.00 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 8:1) to give te title compound (70.0 mg, 123 umol, 60.2% yield) as white solid. LCMS: RT = 0.824 min, [M+H]+= 569.4. [000449] Step L. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-4-amine: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N,N-dimethyl-7,8-dihydro- 5H-pyrano[4,3-d]pyrimidin-4-amine (70.0 mg, 123 umol, 1.00 eq) in dioxane (500 uL) was added HCl / dioxane (4 M, 500 uL, 16.3 eq) at 20 °C under N2, the mixture was stirred at 20 °C for 1 hr. The residue was poured into water (20.0 mL) and stirred for 30 min. The pH was adjusted to around 9 with NaHCO3 aqueous solution and the mixture was extracted with dichloromethane (5.00 mL × 2). The combined organic phase was washed with brine (5.00 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (15.0 mg, 28.6 umol, 23.2% yield) as white solid.1H NMR: (400 MHz, DMSO-d6). δ 9.82 (s, 1 H), 7.44 - 7.43 (d, J = 4.0 Hz, 1 H), 7.30 - 7.26 (t, J = 8.0 Hz, 1 H), 7.16 - 7.15 (d, J = 4.0 Hz, 1 H), 5.49 - 5.46 (m, 1 H), 5.31 - 5.17 (m, 1 H), 5.01 - 4.98 (d, J = 12.0 Hz, 1 H), 4.84 - 4.81 (d, J = 12.0 Hz, 1 H),  3.98 - 3.94 (m, 1 H), 3.86 - 3.83 (m, 1 H), 3.10 - 3.04 (m, 3 H), 3.02 (s, 6 H), 2.98 (s, 1 H), 2.83 - 2.76 (m, 3 H), 2.08 - 1.93 (m, 3 H), 1.82 - 1.71 (m, 3 H), 1.27 - 1.23 (t, J = 8.0 Hz, 3 H); LCMS: RT = 0.791 min, m / z = 525.3 (M+H)+. [000450] EXAMPLE 85(3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3-methylpiperidin- 3-ol [000451] Synthesized according to example 84. The title compound was obtained as white solid.1H NMR: (400 MHz, MeDH-d6). δ 7.63 - 7.59 (m, 1 H), 7.52 - 7.51 (d, J = 4.0 Hz, 1 H), 7.24 - 7.19 (t, J = 8.0 Hz, 1 H), 7.14 (s, 1 H), 5.74 - 5.64 (m, 1 H), 5.36 - 5.22 (m, 1 H), 4.61 (s, 3 H), 4.22 - 4.06 (m, 2 H), 3.60 - 3.51 (m, 1 H), 3.48 - 3.41 (m, 2 H), 3.42 - 3.15 (m, 6 H), 3.03 - 2.99 (m, 1 H), 2.98- 2.83 (m, 2 H), 2.43 - 2.21 (m, 2 H), 2.01 - 1.95 (m, 4 H), 1.94 - 1.60 (m, 5 H), 1.35 - 1.32 (t, J = 8.0 Hz, 3 H), 1.25 - 1.23 (d, J = 8.0 Hz, 3 H); LCMS: RT = 0.799 min, m / z = 595.3 (M+H). [000452] EXAMPLE 86  (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol [000453] Synthesized according to example 84. The title compound was obtained as white solid.1H NMR: (400 MHz, MeOD). δ 7.51 - 7.48 (m, 1 H), 7.39 - 7.42 (dd, J = 4.0 Hz, 1 H), 7.12 - 7.07 (t, J = 8.0 Hz, 1 H), 7.03- 7.03 (d, J = 4.0 Hz, 1 H), 5.57 - 5.54 (m, 1 H), 5.26 - 5.12 (m, 1 H), 5.05 - 4.93 (m, 2 H), 4.49 (s, 3 H), 4.36 - 4.17 (m, 2 H), 4.10 - 3.89 (m, 3 H), 3.16 - 3.02 (m, 4 H), 2.98 - 2.88 (m, 2 H), 2.81 - 2.74 (m, 2 H), 2.23 - 2.00 (m, 6 H), 1.98 - 1.76 (m, 4 H), 1.66 - 1.59 (m, 2 H), 1.23 - 1.20 (t, J = 6.0 Hz, 3 H); LCMS: EW35153-25-P1H, RT = 0.790 min, m / z = 607.4 (M+H). [000454] EXAMPLE 87 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione [000455] Synthesized according to example 84. The title compound was obtained as white solid.1H NMR: (400 MHz, MeOD): δ 7.52- 7.48 (m, 1 H), 7.42 - 7.39 (dd, J = 4.0 Hz, 1 H), 7.12 - 7.08 (t, J = 8.0 Hz, 1 H), 7.03- 7.02 (t, J = 4.0 Hz, 1 H), 5.61 - 5.57 (m, 1 H), 5.27 - 5.14 (m, 1 H), 4.90 - 4.86 (m, 2 H), 4.49 (s, 4 H), 4.15 - 3.96 (m, 3 H), 3.69 - 3.65 (m, 1 H), 3.34 - 3.30 (m, 1 H), 3.18 - 2.92 (m, 5 H), 2.85 - 2.75 (m, 2 H), 2.24 - 2.09 (m, 2 H), 2.04 - 1.97 (m, 2 H), 1.90 - 1.71 (m, 6 H), 1.24 - 1.19 (m, 3 H); LCMS: RT = 0.804 min, m / z = 649.4 (M+H). [000456] EXAMPLE 885-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [000457] Synthesized according to example 84. The title compound was obtained as white solid.1H NMR: (400 MHz, MeOD). δ 7.50 - 7.46 (m, 1 H), 7.36 - 7.35 (dd, J = 4.0 Hz, 1 H), 7.11 - 7.06 (t, J = 8.0 Hz, 1 H), 7.02- 7.01 (d, J = 4.0 Hz, 1 H), 6.48 (s, 1 H), 5.58 - 5.55 (m, 1 H), 5.24 - 5.10 (m, 1 H), 4.94 - 4.91 (d, J = 12.0 Hz, 1 H), 4.68 - 4.66 (m, 3 H), 4.40 - 3.37 (m, 2 H), 3.69 - 3.65 (m, 1 H), 4.04 - 3.89 (m, 3 H), 3.81 - 3.79 (m, 1 H), 3.21 (s, 6 H), 3.17 - 3.14 (m, 2 H), 3.08 - 3.02 (m, 2 H), 2.97 (s, 2 H), 2.91- 2.87 (m, 1 H), 2.85 - 2.75 (m, 2 H), 2.17 - 2.05 (m, 3 H), 2.01  - 1.94 (m, 2 H), 1.88 - 1.84 (m, 2 H), 1.79 - 1.74 (m, 2 H), 1.23 - 1.19 (t, J = 8.0 Hz, 3 H); LCMS: RT = 0.825 min, m / z = 688.4 (M+H). [000458] EXAMPLE 896-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one[000459] Step A. 7-bromo-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2- trifluoroethoxy)quinazoline (3.50 g, 1.0 equiv) in ACN (50 mL) were added Cs2CO3 (9.10 g, 3.0 equiv) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (1.3 g, 1.0 equiv). The reaction was stirred at 60 °C for 3 hours. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 30 mL). The combined layers were purified with column chromatography [SiO2, PE / EtOAc =10 / 1 to 1 / 1] to afford the title compound (2.9 g, 58% yield) as white solid; LCMS (ESI, M+1, M+3): m / z = 482.0, 484.0.  [000460] Step B. 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a mixture of 7-bromo-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)quinazoline (1.40 g, 1.0 equiv), 2-(3-chloro-2-cyclopropyl-5- (methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (983 mg, 1.0 equiv) and K3PO4 (1.85 g, 3.0 equiv) in THF (30 mL) and H2O (6.0 mL) was added CataCXium A Pd G3 (211 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 60 °C for 2 hours. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 30 mL). The combined layers were washed with brine (40 mL), dried over sodium sulfate, concentrated and purified with column chromatography [SiO2, PE / EtOAc =1 / 1 to 0 / 1] to afford the title compound (1.10 g, 48% yield) as yellow solid; LCMS (ESI, M+1): m / z =614.1. [000461] Step C. 3-chloro-4-cyclopropyl-5-(6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)phenol: To a solution of 7-(3- chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (50.0 mg, 1.0 equiv) in ACN(2.0 mL) was added HCl•dioxane (2 M, 2.0 mL). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated under vacuum. The residue was diluted with water (0.1 mL). The mixture was adjusted to pH=7 with saturated NaHCO3 (2 mL) and extracted EtOAc (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (43.0 mg, 92% yield) as yellow solid; LCMS (ESI, M+1): m / z = 570.1. [000462] Step D. 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: To a solution of 3-chloro-4-cyclopropyl-5-(6,8-difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)phenol (33.0 mg, 1.0 equiv) in DMF (2.0 mL) were added K3PO4 (24.5 mg, 2.0 equiv) and 1,8-diazaspiro[3.5]nonan-2-one (20.2 mg, 2.5 equiv). The reaction was stirred at 100 °C for 12 hours. The mixture was filtered and purified with prep-HPLC [Waters Xbridge 150 × 25mm × 5um; mobile phase: water (ammonia hydroxide v / v)- ACN; B%: 22%-52%, 9min] to afford the title compound (8.0 mg, 22% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 7.60 (d, J = 9.2 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 4.14 (d, J = 12.4 Hz, 1H), 3.99 (d, J = 12.0 Hz, 1H), 3.84-3.68 (m, 1H), 2.70-2.53 (m,  2H), 2.44-2.24 (m, 6H), 2.06-1.90 (m, 3H), 1.75-1.41 (m, 11H), 0.71-0.51 (m, 2H), 0.11 (br d, J = 4.4 Hz, 2H); LCMS (ESI, M+1): m / z =610.1. [000463] EXAMPLE 904-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol[000464] Step A.4-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a mixture of 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (60.0 mg, 1.0 equiv) and 6-methyl-1,4-oxazepan-6-ol (25.6 mg, 2.0 equiv) in DMF (1.0 mL) were added 4Å molecular sieve (10.0 mg, 1.0 equiv) and K3PO4 (31.1 mg, 1.5 equiv). The reaction was stirred at 60 °C for 12 hours. The mixture was filtered and purified with prep-TLC [SiO2, DCM / MeOH = 10 / 1] to afford the title compound (35.4 mg, 55% yield) as yellow solid. LCMS (ESI, M+1): m / z = 645.2. [000465] Step B. 4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 4-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35.4 mg, 1.0 equiv) in MeCN (1.0 mL) was added HCl•dioxane (4 M, 1.0 mL). The reaction was  stirred at 0 °C for 0.5 hours. The mixture was concentrated under vacuum. The residue was diluted with water (0.5 mL). The mixture was adjusted to pH=7 with saturated NaHCO3 (1 mL) and extracted with EtOAc (2 × 2 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Waters Xbridge 150 × 25 mm × 5 um; mobile phase: water (ammonia hydroxide v / v)-ACN; B%: 43%-73%, 9 min] to afford the title compound (2.80 mg, 9.0% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.63 (br d, J = 9.2 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 2.4, 6.0 Hz, 1H), 4.68-4.54 (m, 2H), 4.24-4.09 (m, 2H), 3.93-3.77 (m, 2H), 3.70-3.56 (m, 2H), 3.50 (d, J = 12.4 Hz, 1H), 3.47-3.39 (m, 1H), 2.87-2.77 (m, 1H), 2.72-2.56 (m, 5H), 2.19-2.06 (m, 3H), 1.82-1.67 (m, 4H), 1.66-1.55 (m, 2H), 1.10 (s, 3H), 0.62 (br t, J = 6.8 Hz, 2H), 0.17 (br s, 2H); LCMS (ESI, M+1): m / z = 601.3. [000466] EXAMPLE 915-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione[000467] Step A.5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione: To a mixture of 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8- difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline  (60.0 mg, 1.0 equiv) and tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (50.0 mg, 3.2 equiv) in DMF (1.0 mL) were added 4Å molecular sieve (10.0 mg) and K3PO4 (31.1 mg, 1.5 equiv). The reaction was stirred at 60 °C for 12 hours. The mixture was filtered and purified with prep-TLC [SiO2, DCM / MeOH = 10 / 1] to afford the title compound (30.2 mg, 43% yield) as yellow solid. LCMS (ESI, M+1): m / z = 654.2. [000468] Step B. 5-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione: To a solution of 5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)- 6,8-difluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (30.2 mg, 1.0 equiv) in MeCN (1.0 mL) was added HCl•dioxane (4M, 1.0 mL). The reaction was stirred at 0 °C for 0.5 hours. The mixture was concentrated under vacuum. The mixture was diluted with NaHCO3 (2 mL) and extracted with EtOAc (2 × 2 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex C1875 × 30mm × 3um;mobile phase: water(FA)- ACN;B%: 18%-48%,7min; B%: 43%-73%, 9 min] to afford the title compound (5.0 mg, 15.2% yield, 0.2 HCOOH) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 7.62 (dd, J = 1.2, 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.67-6.59 (m, 1H), 4.19-4.06 (m, 2H), 3.85 (qd, J = 7.6, 11.2 Hz, 1H), 3.54 (br t, J = 6.4 Hz, 2H), 3.51-3.45 (m, 4H), 3.21 (br dd, J = 7.2, 11.2 Hz, 2H), 2.22- 2.01 (m, 3H), 1.84-1.63 (m, 6H), 1.37-1.26 (m, 1H), 0.61 (br t, J = 6.8 Hz, 2H), 0.16 (br d, J = 4.4 Hz, 2H); LCMS (ESI, M+1): m / z = 610.3. [000469] EXAMPLE 92 3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol[000470] Step A. 3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (800 mg, 1.2 equiv) and 4Å molecular sieve (1.50 g) in DCM (15 mL) were added DIEA (1.54 g, 3.0 equiv) and 3-azabicyclo[3.2.1]octan-6-ol (320 mg, 1.0 equiv). The reaction was stirred at 0 °C for 0.5 hours. The mixture was diluted with ice-water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with re-crystallization from EtOAc (20 mL) at 25 °C to afford the title compound (600 mg, 68% yield) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 404.1, 406.1. [000471] Step B. 3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 3-(7-bromo-2-chloro-6,8-difluoro-quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (600 mg, 1.0 equiv) in DMSO (5.0 mL) was added KF (1.77 g, 21 equiv). The reaction was stirred at 120 °C for 12 hours. The mixture was filtered. The filtrate was diluted with EtOAc (50 mL). The mixture was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (570 mg, crude) as yellow solid; LCMS (ESI, M+1, M+3): m / z = 387.9, 389.9  [000472] Step C. 3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-2,6,8- trifluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 3-(7-bromo-2,6,8- trifluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (570 mg, 1.0 equiv) and 2-[3-chloro-2- cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (746 mg, 1.5 equiv) in THF (15 mL) and H2O (3.0 mL) were added CataCXium A Pd G3 (214 mg, 0.2 equiv) and K3PO4 (1.5 M, 2.94 mL, 3 equiv). The reaction was stirred at 60 °C for 2.5 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO2, PE / EtOAc = 10 / 1 to 0 / 1] to afford the title compound (600 mg, 79% yield) as yellow solid; LCMS (ESI, M+1): m / z = 520.2. [000473] Step D.3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (32.6 mg, 1.2 equiv) in THF (1.0 mL) was added NaH (15.4 mg, 60% purity, 2.0 equiv) at 0 °C, and then 3-[7-[3-chloro-2-cyclopropyl- 5-(methoxymethoxy)phenyl]-2,6,8-trifluoro-quinazolin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) was added into the mixture. The reaction was stirred at 20 °C for 1 hour. The mixture was quenched with water (10.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organic l...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with 1-4 R1; B is:; Y1is hydrogen, hydroxy, halogen, C1-C4 alkyl, L-C3-C6 cycloalkyl optionally substituted with 1-4 R9, L-heteroaryl optionally substituted with 1-4 R8, L-aryl optionally substituted with 1-4 R8, L-C(O)-NH2, and L-heterocycle optionally substituted with 1-2 oxo (=O) or oxo-containing substituent, and optionally further substituted with 1-2 R8; Y2is hydrogen or C1-C4 alkyl; or Y1and Y2join to form:  where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-; each R1is independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl , triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1- C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; each R2is independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R5)2, -CO2R5, or -CO2N(R5)2; each R3is independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, =CH2, =CH(halogen), =C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, - COC(O)N(R5)2, -CO2R5, or -CO2N(R5)2; R4is hydrogen, halogen or C1 – C3 alkyl; each R5is independently hydrogen or C1-C3 alkyl; each R6is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl; each R7is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -NH2, - NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -CN, aryl, -CH2-S(O)2NH2, or heteroaryl optionally independently substituted with 1-2 C1-C3 alkyl, -CN or C(O)NH2,  two R7on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl), two R7on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R8, heteroaryl optionally substituted with 1-4 R8, aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8, and two R7on non-adjacent atoms optionally join to form a bridge comprising 1-3 members selected from (i) -CH2- optionally substituted with 1-2 substituents selected from hydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-; each R8is independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN; each R9is independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; R10is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2- C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)- or cyclopropyl-CH2-; Z is C or O, wherein if Z is C the 6-membered ring that includes Z is aromatic, and wherein if Z is O the 6-membered ring that includes Z is an oxane; each n is 0-3; o is 1-6; and p is 1-8.

2. The compound or salt of claim 1, wherein: A is aryl, optionally substituted with 1-4 R1; and  Y1and Y2join to form:where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-.

3. The compound or salt of claim 1, wherein: A is heteroaryl, optionally substituted with 1-4 R1; and Y1and Y2join to form:where X is selected from: a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -CH2-CH2-, -CH2-CH2-CH2-, -O-CH2- and -S-CH2-.

4. The compound or salt of any of claims 1-3, wherein B is:.

5. The compound or salt of any of claims 1-3, wherein -L-B is:  .

6. The compound or salt of any of claims 1-2, wherein A is naphthyl.

7. The compound or salt of any of claims 1 and 3, wherein A is indazolyl or benzothiophenyl.

8. The compound or salt of any of claims 1-7, wherein at least one R1is C1-C4 alkyl.

9. The compound or salt of any of claims 1-7, wherein at least one R1is fluorine.

10. The compound or salt of any of claims 1-7, wherein at least one R1is hydroxy.

11. The compound or salt of any of claims 1-7, wherein at least one R2is fluorine.

12. The compound or salt of any of claims 1-7, wherein at least one R3is halogen.

13. The compound or salt of claim 12, wherein said halogen is fluorine.

14. The compound or salt of any one of claims 1-7, wherein at least one of R2and R3is independently selected from the group consisting of =CH2, =CHF, =CF2, 15. The compound or salt of any of claims 1-7, wherein R4is halogen.

16. The compound or salt of claim 15, wherein said halogen is fluorine.

17. The compound or salt of any of claims 1-7, wherein one or both R6are C1-C4 alkyl.

18. The compound or salt of any of claims 1-7, wherein one or both R6are hydrogen.

19. The compound or salt of any of claims 1-7, wherein two R7on the same atom join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with one or more substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl).

20. The compound or salt of any of claims 1-7, wherein two R7on adjacent atoms join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R8; heteroaryl optionally substituted with 1-4 R8; aryl optionally substituted with 1-4 R8, and heterocycle optionally substituted with 1-4 R8.

21. The compound or salt of any of claims 1-7, two R7on non-adjacent atoms optionally join to form a bridge comprising 1-3 members selected from (i) -CH2- optionally substituted with 1-2 substituents selected from hydroxy, cyano, -halogen, C1-C4 alkyl and NH2, (ii) up to one -O-, (iii) up to one -S- and (iv) up to one -NH-; 22. The compound or salt of claim 20, wherein at least one R8is C1-C4 alkyl.

23. The compound or salt of claim 20, wherein at least one R8is hydroxy or C1-C3 alkyl-hydroxy.

24. The compound or salt of claim 20, wherein one or two R8are oxo (=O).

25. The compound or salt of any of claims 1-4, wherein Y1and Y2join to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bound to a fused ring via nitrogen or thiomorpholine.

26. A compound selected from:    and pharmaceutically acceptable salts thereof.

27. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. A method for inhibiting the wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H activity in a cell, comprising contacting the cell in which inhibition of KRas activity is desired with an effective amount of a compound of according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27.

29. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27.

30. The method of claim 29, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg / kg per day.

31. The method of claim 30, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg / kg per day.

32. The method of claim 29, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous  adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial `carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

33. The method of claim 32, wherein the cancer is a KRas G12A-associated cancer.

34. The method of claim 32, wherein the cancer is a KRas G12C-associated cancer.

35. The method of claim 32, wherein the cancer is a KRas G12D-associated cancer.

36. The method of claim 32, wherein the cancer is a KRas G12R-associated cancer.

37. The method of claim 32, wherein the cancer is a KRas G12S-associated cancer.

38. The method of claim 32, wherein the cancer is a KRas G12V-associated cancer.

39. The method of claim 32, wherein the cancer is a KRas G13D-associated cancer.

40. The method of claim 32, wherein the cancer is a KRas Q61H-associated cancer.

41. The method of claim 32, wherein the cancer is a KRas G12A-associated cancer.

42. The method of claim 32, wherein the cancer is associated with at least one of wild type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H.

43. The method of any of claims 32-42, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

44. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H mutation; and (b) administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27.

45. The method of any one of claims 29-44, wherein the administering is done via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac,  intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

46. The method of claim 45, wherein the administration route is oral.

47. The method of claim 45, wherein the administration is intravenous injection.

48. The method of claim 45, wherein the administration route is intramuscular injection.

49. The method of claim 45, wherein the administration route utilizes a delivery device.

50. The method of claim 45, wherein administration is done in a hospital setting.

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